National Cancer Centre Singapore Research Articles

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC

ObjectivesFirst-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. Materials and methodsPatients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). ResultsA total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. ConclusionsOur real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

Impact of a Multidisciplinary Supportive Care Model Using Distress Screening at an Asian Ambulatory Cancer Center: A Cluster Randomized Controlled Trial.

The Accessible Cancer Care to Enable Support for Cancer Survivors (ACCESS) program adopts a multidisciplinary supportive care model with routine distress screening to triage newly diagnosed cancer survivors for additional support on the basis of distress levels. This study aimed to evaluate the clinical impact of ACCESS over 1 year. We performed cluster random assignment at the oncologist level in a 1:1 ratio to receive ACCESS or usual care. Participants 21 years and older, newly diagnosed with breast or gynecologic cancer, and receiving care at National Cancer Centre Singapore were included. Outcomes assessed every 3 months for 1 year included quality of life (QoL) (primary), functioning, physical and psychological symptom burden, and activity levels. Data were analyzed using mixed-effects models. Participants from 16 clusters (control = 90, intervention = 83) were analyzed. The ACCESS program did not significantly improve QoL (primary outcome). However, compared with usual care recipients, ACCESS recipients reported higher physical functioning (P = .017), role functioning (P = .001), and activity levels (P < .001) at 9 months and lower psychological distress (P = .025) at 12 months. ACCESS recipients screened with high distress had poorer QoL, lower role and social functioning, and higher physical symptom distress at 3 months but had comparable scores with ACCESS recipients without high distress after 12 months. Compared with usual care, participation in the ACCESS program did not yield QoL improvement but showed earlier functioning recovery related to activities of daily living and reduced psychological distress. Routine distress screening is a promising mechanism to identify survivors with poorer health for more intensive supportive care.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1&lt;12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

The employment of art therapy to develop empathy and foster wellbeing for junior doctors in a palliative medicine rotation - a qualitative exploratory study on acceptability

BackgroundThe interdisciplinary realm of medical humanities explores narratives and experiences that can enhance medical education for physicians through perspective-taking and reflective practice. However, there is a gap in comprehension regarding its appropriateness at the postgraduate level, especially when utilising art therapists as faculty. This study aims to assess the acceptability of an innovative art therapy-focused educational initiative among junior doctors during a palliative care rotation, with the goal of cultivating empathy and promoting well-being.MethodsA qualitative research project was conducted at the Division of Supportive and Palliative Care (DSPC) in the National Cancer Centre Singapore (NCCS). The study involved the recruitment of junior doctors who had successfully completed a three-month palliative care rotation program, spanning from January 2020 to April 2021. In a single small-group session lasting 1.5 h, with 3 to 4 participants each time, the individuals participated in activities such as collage making, group reflection, and sharing of artistic creations. These sessions were facilitated by an accredited art therapist and a clinical psychologist, focusing on themes related to empathy and wellbeing. To assess the acceptability of the program, two individual interviews were conducted three months apart with each participant. An independent research assistant utilised a semi-structured question guide that considered affective attitude, burden, perceived effectiveness, coherence, and self-efficacy. Thematic analysis of the transcribed data was then employed to scrutinise the participants’ experiences.ResultsA total of 20 individual interviews were completed with 11 participants. The three themes identified were lack of pre-existing knowledge of the humanities, promotors, and barriers to program acceptability.ConclusionsThe participants have mixed perceptions of the program’s acceptability. While all completed the program in its entirety, the acceptability of the program is impeded by wider systemic factors such as service and manpower needs. It is vital to address these structural limitations as failing to do so risks skewing current ambivalence towards outright rejection of future endeavours to integrate humanities programs into medical education.

A digital self-reported G8 screening tool: A comparison study

Background Geriatric assessment (GA) has been shown to be pivotal to the prognosis of elderly cancer patients. A G8 screening tool could act as a potential surrogate to identify patients who would benefit from further GA in a busy oncology clinic and a digital version would allow for a wider application. Objectives To develop a digital self-reported version of G8, and to compare its outcomes with in-person G8 administered by a healthcare professional. Methods A total of 483 cancer patients aged 70 years and older who received an in-person G8 assessment at the National Cancer Centre Singapore (NCCS) clinic, and another 544 who completed the digital self-reported G8 were analysed. Total G8 score ≤14 was defined as positive screen. Results Response rate of the digital self-reported G8 was 50%. Median G8 total score was lower among online screeners than in-person screeners (11 vs 12.5, p &lt; 0.001). The odds of a G8 positive screen among online screeners was higher than that of in-person screeners on multivariable logistic regression analysis (odds ratio = 1.56, 95% CI 1.08-2.26). Some 20 in-person screeners had also completed the digital self-reported G8, and the agreement between their in-person and online G8 total scores was high (concordance correlation coefficient = 0.798, 95% CI 0.635-0.962). Conclusions A digital self-reported G8 is feasible. However, given the higher positive screen rate among the online screeners, replacement of the in-person G8 with the digital self-reported G8 should be implemented only after more conclusive evidence on the agreement between in-person and online G8 score is available.

Assessing the financial impact of cancer drug list (CDL) implementation on patients receiving chemotherapy in an ambulatory cancer centre in Singapore

Background On 1st September 2022, the Cancer Drug List (CDL) was implemented to ensure the long-term affordability of chemotherapy and insurance premiums. This project aimed to determine the financial impact of CDL on out-of-pocket expenses (OOPE), acceptability and financial toxicity (FT) after CDL implementation. Methods A cross-sectional study was conducted at National Cancer Center Singapore. We analyzed OOPE before and after implementation of CDL by reviewing billing transactions in Aug-Sept 2022. Acceptability and FT were determined using theoretical framework of acceptability (TFA) and COmprehensive Score for financial Toxicity (COST) tool respectively via survey. Results Of the 314 patients finalized bills examined, majority (68.8%) experienced no change in their OOPE, and 69.1% had no OOPE. Most patients (72.6%) were unaware of implementation of CDL. Among patients aware of CDL, majority (61.9%) were accepting, but unsure on how it benefits them. FT was reported as low (mean COST score = 22.4 ± 9.9), and patients ≥65 years old or have at least pre-university education were less likely to experience FT. Conclusion Despite best efforts from policymakers, it is challenging to achieve a one-size fits funding or subsidy framework that can cater to the needs of all patients. Some groups of patients would inevitably still experience high OOPE and FT due to their personal or clinical circumstances. Patients can be better empowered to seek financial assistance or resources.

Correlation of Neutrophil-Lymphocyte and Albumin-Globulin Ratios With Outcomes in Patients With Breast Cancer Undergoing Neoadjuvant Chemotherapy or Upfront Surgery.

Higher neutrophil-lymphocyte ratio (NLRs) indicate a pro-inflammatory state and are associated with poor survival. Conversely, higher albumin-globulin ratio (AGRs) may be associated with improved prognosis. We aimed to investigate the association between NLR and AGR and prognosis and survival in patients with breast cancer. This retrospective study included all patients with stage I-III breast cancer between 2011 and 2017 in Singapore General Hospital and National Cancer Center Singapore. Multivariate logistic regression analysis of NLR, AGR, age, stage, grade, and subtype was performed. Survival data between groups were compared using Cox regression analysis and log-rank tests. A total of 1,188 patients were included, of whom 323 received neoadjuvant chemotherapy (NACT) and 865 underwent upfront surgery. In patients who underwent NACT, a higher AGR was significantly associated with a higher pCR rate (cut-off > 1.28; odds ratio [OR], 2.03; 95% confidence interval [CI], 1.13-3.74; p = 0.020), better DFS (cut off > 1.55; hazard ratio [HR], 0.37; 95% CI, 0.16-0.85; p = 0.019), and better CSS (cut off > 1.46; HR, 0.39; 95% CI, 0.17-0.92; p = 0.031). Higher NLR was significantly associated with worse DFS (cut off > 4.09; HR, 1.77; 95% CI, 1.07-2.91; p = 0.026) and worse CSS (cut off > 4.09; HR, 1.98; 95% CI, 1.11-3.53; p = 0.021). In patients who underwent upfront surgery, higher AGR correlated with significantly better OS (cut off > 1.17; HR, 0.54; 95% CI, 0.36-0.82; p = 0.004) and higher NLR correlated with worse OS (cut off > 2.38; HR, 1.63; 95% CI, 1.09-2.44; p = 0.018). NLR and AGR are useful in predicting the response to NACT as well as prognosis of patients with breast cancer. Further studies are needed to explore their value in clinical decision making.

Using Deauville Scoring to Guide Consolidative Radiotherapy in Diffuse Large B-Cell Lymphoma

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults. Although consolidative radiotherapy (RT) is often administered in DLBCL, guidelines concerning its usage remain unclear. International guidelines recommend using positron emission tomography (PET) with 18F-fluorodeoxyglucose to stage and assess remission in DLBCL patients. We aimed to assess the value of end-of-treatment PET scans, interpreted using the Deauville score (DV), in guiding the utilization of consolidative RT. This approach may help spare low-risk DLBCL patients from unnecessary RT. Methods All DLBCL patients diagnosed from 2010-2022 at National Cancer Centre Singapore with DV measured at the end of first line chemotherapy were included. DV 1-3 patients were classified as low-DV risk and DV 4-5 patients as high-DV risk. Primary endpoint was time-to-progression (TTP), defined as the time from diagnosis to progression or relapse of DLBCL, or death due to DLBCL or treatment-related factors. Patients without these events were censored at their last follow-up. Cox proportional hazards regression was used to assess the association of TTP with various covariates. The predictive value of DV risk group was analyzed by including an interaction term between receipt of RT and DV risk group in the Cox model. Effect estimates were summarized using hazard ratios (HRs) and 95%-confidence intervals (95%CI). Results A total of 349 patients were analyzed, of which 80 were treated with RT (RT-treated) and 269 without RT (RT-omitted). The mean age of the whole cohort was 59.8 years (standard deviation 15.9 years). Compared with RT-omitted patients, there were higher percentages of RT-treated patients with stage 1-2 disease (61% vs 43%, p=0.007), elevated lactate dehydrogenase (85% vs 71%, p=0.039) and bulky disease (25% vs 10%, p=0.003). On average, RT-treated patients also had lower baseline hemoglobin levels compared to RT-omitted patients (11.7 g/dL vs 12.2 g/dL, p=0.038). The median follow-up time was 38.1 months (interquartile range 34.0-42.3 months). As a higher proportion of RT-treated patients was diagnosed later than RT-omitted patients, median follow-up times were significantly different between the two groups (RT-treated: 25.4 months vs RT-omitted: 42.3 months, p&amp;lt;0.001). TTP was comparable between RT-treated and RT-omitted patients (HR 0.81; 95%CI 0.45-1.48; p=0.492) (Table 1). When sub-grouped by DV risk group, RT was associated with a significant improvement in TTP amongst the high-DV risk patients (HR 0.33; 95%CI 0.13-0.88; p=0.027), but not the low-DV risk patients (HR 0.85; 95%CI 0.40-1.81; p=0.670; interaction's p=0.133) (Figure 1). This subgroup analysis result remained the same after adjusting for International Prognostic Index, presence of B symptoms, bone marrow involvement and hemoglobin levels on multivariable analysis (high-DV risk: adjusted HR 0.29; 95%CI 0.11-0.80; p=0.017 vs low-DV risk: HR 0.86; 95%CI 0.40-1.86; p=0.707; interaction's p=0.087). To examine the impact of the different follow-up durations between the RT-treated and RT-omitted patients on the subgroup analysis, we performed a sensitivity analysis censoring TTP at 24 months. In this sensitivity analysis, RT was again associated with a significant improvement in TTP amongst the high-DV risk patients (adjusted HR 0.29; 95%CI 0.10-0.82; p=0.019), but not those with low-DV risk (adjusted HR 0.70; 95%CI 0.27-1.86; p=0.477; interaction's p=0.217). Conclusion Our study suggests that DLBCL patients who received first line chemotherapy with end-of-treatment PET-CT DV 1-3 may not require consolidative RT. This observation will need longer follow-up duration to ascertain the use of DV as a potential marker to guide patient selection for consolidative RT. We will continue to follow these patients up for overall survival.

337P Demographic patterns and survival outcomes of patients with T and NK-cell lymphoma at the National Cancer Centre Singapore

337P Demographic patterns and survival outcomes of patients with T and NK-cell lymphoma at the National Cancer Centre Singapore

Professional identity formation amongst peer-mentors in a research-based mentoring programme

BackgroundMentoring plays a pivotal yet poorly understood role in shaping a physician’s professional identity formation (PIF) or how they see, feel and act as professionals. New theories posit that mentoring nurtures PIF by functioning as a community of practice through its structured approach and its support of a socialisation process made possible by its assessment-directed personalized support. To test this theory and reshape the design, employ and support of mentoring programs, we evaluate peer-mentor experiences within the Palliative Medicine Initiative’s structured research mentoring program.MethodsSemi-structured interviews with peer mentors under the Palliative Medicine Initiative (PMI) at National Cancer Centre Singapore were conducted and triangulated against mentoring diaries to capture longitudinal data of their PMI experiences. The Systematic Evidence-Based Approach (SEBA) was adopted to enhance the trustworthiness of the data. SEBA employed concurrent content and thematic analysis of the data to ensure a comprehensive review. The Jigsaw Perspective merged complementary themes and categories identified to create themes/categories. The themes/categories were compared with prevailing studies on mentoring in the Funnelling Process to reaffirm their accuracy.ResultsTwelve peer-mentors participated in the interviews and eight peer-mentors completed the mentoring diaries. The domains identified were community of practice and identity work.ConclusionsThe PMI’s structured mentoring program functions as a community of practice supporting the socialisation process which shapes the peer-mentor’s belief system. Guided by a structured mentoring approach, stage-based assessments, and longitudinal mentoring and peer support, peer-mentors enhance their detection and evaluation of threats to their regnant belief system and adapt their self-concepts of identity and personhood to suit their context. These insights will help structure and support mentoring programs as they nurture PIF beyond Palliative Medicine.

Cancer patients' experience of receiving variant of uncertain significance results: An Asian perspective.

Due to a lack of ancestry-matched, functional, and segregation data, Asians have a higher rate of receiving a variant of uncertain significance (VUS) result following panel testing. Managing VUS results presents challenges, as it often leads to increased anxiety and distress among cancer patients undergoing genetic testing. This exploratory study aims to investigate the experience of Asian cancer patients upon receiving a VUS result. A qualitative, semi-structured interview study was conducted, involving cancer patients who had received a VUS result through the Cancer Genetics Service of the National Cancer Centre Singapore. Twenty participants were interviewed, and their responses were transcribed and analyzed using thematic analysis to identify key themes. Thematic analysis revealed five major themes: (1) VUS results are interpreted as uncertain outcomes; (2) a VUS result provides relief and prompts positive behavioral adjustments; (3) patients employ fatalism and religion as coping mechanisms to navigate uncertainty; (4) genetic counselors, family, and the community offer reassurance and support; (5) patients value updates on variant classifications for future management. While this novel study provides unique insights into the perspectives of Asian patients who receive VUS results, it also highlights patients' effective management of VUS results and uncertainty, which has implications for improving counseling practices in Asia. Emphasis must be placed on accurate interpretation and clear communication of VUS results to dispel the possibility of misconceptions, misdiagnosis, and mismanagement in cancer care.

Circulating tumour DNA (ctDNA) burden quantified through low-pass whole genome sequencing as an early pharmacodynamic biomarker of therapeutic response in patients enrolled on phase 1 trials.

23 Background: Early phase trials are conducted to determine the recommended dose and safety of an investigational therapy. Targeted therapies and immunotherapy may not always have dose-dependent toxicities. Therefore, dose finding is increasingly reliant on optimal biological dosing. Pharmacodynamic biomarkers are increasingly important to demonstrate proof of concept. Using ctDNA allows for dynamic and early tumour assessments compared to imaging. We sought to evaluate ctDNA as an early pharmacodynamic biomarker of therapeutic response. Methods: Patients (pts) enrolled on phase 1 trials at the National Cancer Centre Singapore were prospectively consented to collect serial blood samples at defined timepoints (pre-treatment, mid-cycle 1, end of cycle 1, and with subsequent imaging evaluations). ctDNA burden was quantified using low pass whole genome sequencing (lpWGS) with both established (ichorCNA) and novel (cell-free DNA degradation) bioinformatic analyses of ctDNA burden, and targeted panel sequencing. Early kinetics of ctDNA burden prior to imaging evaluation was evaluated as response (reduction in ctDNA burden) versus progression (increase in ctDNA burden). Results: Between May 2021 to Oct 2022, 68 plasma samples (median 3, range 2-5) were collected from 22 pts. Median age was 56 years (range 37-77) and 73% were male. Pts were enrolled on trials of targeted therapy (55%), immunotherapy (40%) or combinations of both (5%). Common tumour types were lung (36%), colorectal (23%) and pancreatic (9%) cancer. Best response on phase 1 trial as per imaging and RECIST v1.1 was partial response (PR) in 9%, stable disease (SD) in 45%, progressive disease (PD) in 27% and not evaluable (NE; taken off trial early due to toxicity) in 18%. Quantification of ctDNA burden using cell-free DNA fragment length pattern demonstrated enhanced limit of detection in detecting baseline ctDNA compared to cell-free DNA copy number profile based ichorCNA method (100% vs 59%). For pts on targeted therapies, early kinetics of ctDNA burden indicated ctDNA response in 9/13 pts, with subsequent imaging showing PR (n=2), SD (n=2), PD (n=2) or NE (n=3). In the remaining 4/13 pts on targeted therapies with early ctDNA progression, subsequent imaging showed SD (n=3) or NE (n=1). For pts on immunotherapy, early ctDNA progression was seen in 8/10 pts, with subsequent imaging showing SD (n=5) and PD (n=3). Patient enrolment and sample analysis is ongoing to further validate these initial findings and updated data will be presented. Conclusions: Early ctDNA evaluation via lpWGS may represent an early pharmacodynamic biomarker of therapeutic response. ctDNA has the potential to provide early proof of concept, particularly for targeted therapies, that may influence subsequent decisions for dose determination.

Automated classification of disease response in radiology reports using natural language processing.

108 Background: Classification of disease response is an essential task in cancer research and needs to be done at scale. Automating this process can improve efficiency in the generation of real-world evidence, potentially leading to better patient outcomes. We aim to develop and evaluate Natural Language Processing (NLP) models for this task. Methods: Using 6203 computed tomography (CT) and 1358 magnetic resonance imaging (MRI) reports from 587 patients with lung cancer of all stages seen at the National Cancer Centre Singapore (NCCS), we trained four NLP models (BioBERT, RadBERT-RoBERTA, BioClinicalBERT, GatorTron) to classify the reports into one of four categories: no evidence of disease, stable disease, partial response or disease progression. Model output was compared against human-curated ground truth and performance was evaluated by accuracy. Results: Of the 4 models, GatorTron performed the best (accuracy = 97.1%), followed by RadBERT-RoBERTA (accuracy = 96.2%), BioBERT (accuracy = 94.2%), with BioClinicalBERT being last (accuracy = 90.4%). NLP Model runtimes for the dataset were relatively short, with BioBERT and BioClinicalBERT taking 3 minutes per epoch, RadBERT-RoBERTA taking 6 minutes per epoch, and GatorTron taking 10 minutes per epoch on a single central processing unit (CPU). Conclusions: We have demonstrated the effectiveness of NLP models for classifying disease responses in radiology reports of lung cancer patients. This has the potential to help derive progression-free survival for real-world evidence generation.

Heterogeneity of PD-L1 expression among resected EGFR-mutated NSCLC and prognostic implications.

143 Background: The predictive value of PD-L1 score to select patients for adjuvant immunotherapy among epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains controversial, confounded by the use of different assays across trials. We sought to compare the concordance between 3 PD-L1 antibodies among resected EGFR-mutated NSCLC, evaluate intra-tumoral heterogeneity (ITH) and implications on survival outcomes. Methods: Tissue microarrays were constructed from patients with AJCC7 Stage IA-IIIA EGFR-mutated NSCLC who underwent surgery 1/1/2010 – 31/12/2019 at National Cancer Centre Singapore. Patients who received neoadjuvant therapy were excluded. Three 1mm tumor cores per patient were obtained to study ITH, defined as discordant tumor proportion score (TPS) in ≥2/3 cores. TPS was evaluated by 3 independent pathologists for 3 PD-L1 antibodies (SP263, SP142, 22C3) and analysed in tertiles of &lt;1%, 1-49% and ≥50%. Median TPS score across 3 cores for each pathologist per assay was used to assess concordance between assays with Cohen’s kappa test, which was also used to assess agreement between pathologists. Disease-free survival (DFS) and overall survival (OS) were tabulated using Kaplan-Meier method. Results: A total of 218 patients were included. Stage IA comprised 45%(99/218), IB 24%(53/218), II 17%(37/218) and IIIA 13%(29/218). Females made up 65%(142/218), never smokers 84%(183/218) and 71%(155/218) were acinar subtype adenocarcinomas. Ex19del was detected in 47%(103/218) and L858R in 39%(86/218). Distribution by PD-L1 TPS was 85%(185/218) vs 91%(198/218) vs 97%(212/281) for &lt;1%, 13%(28/218) vs 8%(17/218) vs 3%(6/218) for 1-49%, and 2%(5/218) vs 1%(3/218) vs 0% for ≥50%, using SP263, 22C3 and SP142 respectively (p&lt;0.001). Pairwise comparison of TPS scores revealed highest concordance between SP263 and 22C3 (Kappa 0.631), followed by 22C3 and SP142 (Kappa 0.361), and SP263 and SP142 (Kappa 0.192). Agreement between pathologists was excellent across all 3 assays, with median Cohen’s kappa of 1 (range 0.972 – 1). ITH was observed in 13%(29/218), with 5 patients having differing TPS scores in all 3 cores. Discordance was highest among TPS 1-49% at 96%(27/28), followed by ≥50% at 40%(2/5) and least among &lt;1% at 0% (p&lt;0.01). Compared to those with concordant TPS scores across all 3 cores, 5-year DFS (60% vs 47%, p=0.15) and 5-year OS (81%% vs 71%, p=0.043) were inferior for patients with ITH. Conclusions: Concordance of PD-L1 TPS was highest among SP263 and 22C3 and lowest for SP263 and SP142, with low inter-observer variability between pathologists. Heterogeneous PD-L1 expression within tumors was seen in 13% of patients and significantly correlated with inferior OS. Our findings support the relative interchangeability of SP263 and 22C3 among resected EGFR-mutated NSCLC but not SP142, while ITH in PD-L1 expression may represent a novel negative prognostic biomarker.

Determining acceptance and perceptions of chemotherapy dose banding in an ambulatory cancer centre.

Despite the advantages of dose banding (DB) and numerous plans to adopt this practice, uptake of DB is still poor. As opinions of healthcare professionals were deemed essential in DB's acceptance, this study surveyed key stakeholders to determine the acceptance, facilitators, and barriers of DB in chemotherapy to improve its implementation. A cross-sectional study at the National Cancer Centre Singapore, involving physicians, nurses, and pharmacy staff, was conducted in February 2022. The Theory of Planned Behaviour was adapted to design a survey questionnaire to obtain the acceptance, facilitators, and barriers of DB. Additional questions on maximum acceptable dose variance and essential criteria for selecting drugs for DB were included. A total of 93 participants responded, with a mean 9.75 ± 7.37 years of clinical experience. Less than half have heard of DB while few had prior experience. Drug cost was the top selection criteria for DB, followed by toxicity, therapeutic index, frequency of use and drug wastage. Acceptance rate of DB was 41.9%, with majority agreeing to use DB in various drugs but to determine patient suitability before usage. Being greatly affected by subjective norms, having a positive outlook for DB's impacts, and no effect on toxicity significantly influenced acceptance. Prior to implementing DB at the institutional level, educational training addressing concerns over toxicity, and providing technological support can help improve acceptance. Future studies can involve patients' perspectives and more institutions for greater diversity in opinions.

Quantifying chemotherapy wastage in an ambulatory cancer centre in Singapore.

To ensure the efficient use of chemotherapy drugs, chemotherapy wastage is an area that can be investigated. This study aims to quantify current parenteral chemotherapy wastage and estimate parenteral chemotherapy wastage when dose banding is executed, using a chemotherapy wastage calculator in an ambulatory cancer centre. The study also examines the variables that significantly predict the total cost of chemotherapy wastage, investigates the reasons for wastage, and explores opportunities to reduce wastage. Data were collected from the pharmacy in National Cancer Centre Singapore over 9 months retrospectively. Chemotherapy wastage is the sum of wastage in the preparation phase and potential wastage in the administration phase. The calculator was created using Microsoft Excel and generated chemotherapy wastage in terms of cost and amount (mg) and analysed the reasons for potential wastage. The calculator reported a total of 2.22 million mg of chemotherapy wastage generated over 9 months, amounting to $2.05 million (Singapore Dollars, SGD). Regression analysis found that the cost of drug was the only independent variable that significantly predicted the total cost of chemotherapy wastage (P = 0.004). The study also identified low blood count (625 [29.06%]) as the top reason for potential wastage and no-show ($128,715.94 [15.97%]) as the reason that incurred the highest cost of potential wastage. The pharmacy has generated a considerable amount of chemotherapy wastage over 9 months. Interventions in both the preparation and administration phases are required to reduce chemotherapy wastage. The use of the chemotherapy wastage calculator in pharmacy operations could guide efforts to reduce chemotherapy wastage.

Elucidating the genomic and transcriptomic landscape of L858R vs ex19del EGFR-mutated NSCLC.

8530 Background: Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is heterogeneous and L858R derive less benefit from osimertinib than ex19del in both the metastatic and adjuvant setting, which remains poorly understood. We sought to examine the genomic and transcriptomic features of L858R vs ex19del. Methods: Consecutive patients with AJCC7 Stage IA-IIIA EGFR-mutated NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent surgery at National Cancer Centre Singapore were included. Patients who received neoadjuvant therapy were excluded. Fresh frozen tumour and normal samples were subject to whole exome sequencing (WES) at 400X and 100X coverage respectively, with approximately 50 million paired-end reads for RNA-seq per sample. Wilcoxon and Fisher’s exact test were used for association analysis. Results: A total of 203 patients were included. Median age at diagnosis was 66, 66.0% (134/203) were females and 84.2% (171/203) never-smokers. Stage IA comprised 44.3% (90/203), IB 28.6% (58/203), II 15.8% (32/203) and IIIA 11.3% (23/203). Median tumour mutational burden (TMB) was 1.3 mutations/megabase (range 0.3 – 44.3). Ex19del represented 46.3% (94/203) and L858R 41.9% (85/203). Whole genome doubling (WGD) was found in 70.0% (142/203) and was more common in TP53-mutated compared to TP53-wildtype (81.1% vs. 63.6%, p=0.01). TP53 mutations were more common in stage II/IIIA tumours compared with stage IB and IA (50.9% vs 32.8% vs 30.0%, p=0.035). Comparing ex19del and L858R, there was no difference in stage distribution (p=0.337), proportion of TMB≥10 (1.1% vs 5.9%, p=0.103), number of cancer co-driver mutations (p=0.174), TP53 mutations (39.4% vs 32.9%, p=0.437) and WGD (69.1% vs 76.5%, p=0.316). L858R had a higher incidence of smoking mutational signature (median 0.35 vs 0.28, p=0.018) compared to ex19del despite similar smoking history (15.3% vs 12.8%, p=0.67), whereas APOBEC mutational signature was higher in ex19del (median 0.06 vs 0.04, p=0.015). L858R tumors were associated with a higher incidence of co-mutations in RBM10 (21.2% vs 6.38%, p=0.004), RNF213 (10.6% vs 1.06%, p=0.007) and amplification of NTHL1 (15.3% vs 2.13%, p=0.001) and AXIN1 (17.6% vs 3.19%, p=0.002) compared to ex19del. Transcriptomic subtype differed significantly by EGFR mutation with a higher representation of TRU subtype among L858R than ex19del (51.0% vs 35.3%, p=0.010), while GEP score was similar (median 0.189 vs 0.325, p=0.122). Conclusions: L858R have distinct co-mutations and copy number alterations compared to ex19del, in addition to a higher representation of smoking mutational signature and TRU subtype. TP53 co-mutations are more frequently observed in higher stage tumours and are associated with WGD. Our findings highlight the molecular heterogeneity of resected EGFR-mutated NSCLC, which could contribute to the differential outcomes to adjuvant osimertinib between ex19del and L858R.

Operational Challenges of an Asia-Pacific Academic Oncology Clinical Trial.

The Asia-Pacific (APAC) region is a major focus for multinational clinical trials, although its cultural, linguistic, economic, and regulatory diversity pose significant challenges for trial conduct, particularly for academic clinical trials. We describe our experience running the investigator-initiated phase III randomized, fully accrued, Aspirin for Dukes C and high-risk Dukes B Colorectal cancer trial (ASCOLT, ClinicalTrials.gov identifier: NCT00565708, N = 1,587), studying the benefit of aspirin in resected high-risk colorectal cancer. ASCOLT opened in 2008 and is the first large academic adjuvant trial fully conducted in the APAC region. Centrally coordinated by the Trial Management Team at the National Cancer Centre Singapore, it has involved 74 sites across 12 APAC countries/regions, including five middle-income countries. Challenges encountered included regulatory complexity, communication and logistical barriers, limited funding and resources, disparate experience and infrastructure across sites, recruitment holds because of changes in local laws, patient attrition, and disruptions caused by the COVID-19 pandemic. Over 100 contracts and 49 ethics board reviews were required, contributing to a lengthy prestudy preparation time of 2 years and start-up times of approximately 6 months per site. Some of the mitigating actions included engaging local cooperative groups (eg, the Australasian Gastro-Intestinal Trials Group in Australia and New Zealand) and seven contract research organizations to manage sites, regular communication with the central team, transition to electronic data management, and a centralized drug-dispensing system. To ensure an efficient and patient-centered clinical trials environment in the APAC region and sustained growth, we suggest coordinated approaches to harmonize regulatory processes, APAC academic oncology trials consortia to streamline processes and provide governance, and ongoing commitment from governments, funding agents, and industry.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Angioimmunoblastic T cell Lymphoma (AITL) is a subtype of peripheral T cell lymphoma and prognosis is generally felt to be poor. Molecular characteristics differentiating good or poor risk AITL has not been identified. In our Asian multicentre study, we investigate the clinical prognostic factors affecting the outcomes of our AITL patients. We also interrogate the gene expression profiles in our patients to identify if there may be different immune and cell signalling signatures in different risk groups. Methods: Patients who were diagnosed with AITL and seen at National Cancer Centre Singapore, Singapore General Hospital and National University Cancer Institute, Singapore between June 1999 and December 2019 were retrospectively analysed. Relevant demographical and clinical characteristics were collected. Outcomes of interest were that of 5-year overall survival (OS) and 5-year progression free survival (PFS). Kaplan-Meier curves were plotted to estimate survival for each individual clinical parameter. Parameters found to be significant on univariate analysis were subsequently used in the generation of multivariate cox regression models. NanoString PanCancer IO360 panel (NanoString Technologies, Seattle, WA, USA) was used to interrogate gene expression on AITL FFPE tissue, following manufacturer’s protocol using the nCounter platform. Results: A total of 174 patients were identified. Median duration of follow up was 20.4 months. Median PFS and OS was 1.8 years and 5.6 years respectively. In multivariate analyses, Age >60, bone marrow Involvement, Total white cell count and serum Lactate dehydrogenase were associated with poorer PFS and OS. A prognostic index (AITL-PI) differentiated patients into low (0–1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3–4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). Gene expression studies performed in 23 patients found disparate immune cell type profiles and oncogenic signalling pathway signatures in the low risk as compared to the intermediate and high-risk groups. In the low risk group, neutrophilic, T-regulatory and Th-1 cell profiles were predominant whereas cytotoxic cell profile was predominant in the intermediate and high-risk groups. The low risk group was more active in the myeloid compartment, WNT, cytokine and chemokine, TGF-β and hedgehog signalling pathways whereas cytotoxicity, interferon and lymphoid compartment signalling signatures returned higher in the intermediate and high-risk groups. The research was funded by: NCCS Cancer Fund (Research) (NCCSCF-R-YR2021-JUN-SSD1), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Awards (TA21jun-0005 and TA20nov-0020), Large Collaborative Grant (OFLCG18May-0028), and Collaborative centre grant (TETRAD II). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

COVID-19 vaccination uptake and safety profile among germline BRCA1 and BRCA2 pathogenic variant carriers in Singapore

BackgroundAlthough Singapore is one of the highest vaccinated countries in the world, vaccine hesitancy remains in a subpopulation, including individuals with cancer predisposition syndromes. At the Cancer Genetics Service National Cancer Centre Singapore, we see patients with germline genetic alterations, most being BRCA1/2 pathogenic/likely pathogenic variant (PV/LPV) carriers. While reported safe for cancer patients, there are limited studies addressing the safety profile and outcomes of COVID-19 vaccination among individuals with germline PV/LPV in cancer predisposition genes such as BRCA1/2. This study aims to evaluate the outcomes of COVID-19 vaccination among germline PV/LPV carriers in BRCA1/2.MethodsWe conducted a phone call survey of COVID-19 vaccination uptake and toxicity in a prospective cohort of 189 participants with germline BRCA1/2 PV/LPV between 1st Sept 2021 and 30th Sept 2021. We collected demographics data including gender, race, age, history of cancer, types of cancer, and number of cancers. Statistical difference in baseline demographics between responders with history of cancer and those without were assessed using Chi-square, Fisher’s exact and independent t-test analysis. Logistic regression was used to evaluate effect of demographics on the occurrence of post-vaccination side effects.ResultsAmong 189 BRCA1/2 PV/LPV carriers responded, 97 carried PV/LPV in BRCA1 and 92 in BRCA2. Majority were vaccinated (89.5%) and had completed the two-dose vaccine schedule, with 7 (4.1%) received only one dose. The most common post-vaccination side effects was myalgia (56.5%) followed by fever (40.2%), headache (16.3%) and fatigue (11.2%). There were no major severe side events. Evaluation by logistic regression showed that the occurrence of side effects was not affected by PV/LPV gene (BRCA1 or BRCA2), gender, race, age or history of cancer.ConclusionThe post-vaccination side effects profile among individuals with germline PV/LPV in BRCA1/2 is consistent with the Singaporean general population, hence recommendations for COVID-19 vaccination for these individuals should not differ from non-carriers and should be encouraged by their healthcare providers.