Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

BACKGROUND: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. METHODS: This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. RESULTS: The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p < .0001). CONCLUSIONS: ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

Far from the truth: Real-world treatment patterns among newly diagnosed metastatic prostate cancer in the era of treatment intensification.

OBJECTIVES: Real-world uptake of treatment intensification (TI) with novel hormonal agents (NHA) or chemotherapy as treatment of metastatic prostate cancer remains low outside of trial settings. We aim to report the prescription patterns and treatment outcomes of de novo metastatic hormone-sensitive prostate cancer (mHSPC) in a tertiary institution. METHODS: This is a retrospective cohort study using real-world data from a prospectively maintained prostate cancer registry. We selected patients newly diagnosed with mHSPC from January 2016 to December 2020. Clinicopathological parameters were recorded to determine their impact on prescription patterns. RESULTS: In total, 585 patients with metastatic prostate cancer were identified. Prescription of NHA increased from 10.5% (2016) to 50.4% (2020), but that of chemotherapy declined. Factors associated with TI were (1) baseline health status: Charlson Comorbidity Index 0-2, ECOG 0-1, age ≤ 65, (2) disease burden: PSA (>400, CHAARTED high volume disease, p = 0.004), development of systemic complications and (3) physician factor: primary physician being uro-oncologist and medical oncologist versus general urologist. Patients with TI had a longer mean time to castration-resistant prostate cancer (45.0 vs. 32.5 months, HR 0.567, 95% CI: 0.441-0.730, p < 0.001) and overall survival (55.3 vs. 46.8 months, HR 0.612, 95% CI, 0.447-0.837, p = 0.001). CONCLUSION: This study demonstrated the trend of treatment prescription of mHSPC and factors contributing to the use of TI. TI improved mean time to CRPC and OS.

Androgen receptor pathway inhibitors, prostate cancer, and older adults: a global Young International Society of Geriatric Oncology drug review.

Prostate cancer is a disease of older adults that has undergone a significant therapeutic paradigm shift in the last decade with the emergence of novel androgen receptor pathway inhibitors (ARPis). One of the more commonly used ARPis is enzalutamide. This drug, along with darolutamide and apalutamide, initially received approvals in the metastatic castrate-resistant prostate cancer setting but is now utilized frequently in the metastatic castrate-sensitive and non-metastatic castration-resistant settings. Landmark phase III data illustrating ARPi efficacy in older adults are limited to those with excellent performance status. However, its role in unfit older prostate cancer patients remains to be explored in the context of a narrative review. This first-of-its-kind drug review aims to shed light on the most up-to-date evidence behind the unique toxicity profile of ARPis in the context of geriatric vulnerabilities such as cognitive and functional impairment, along with potential solutions and supporting evidence that exists to circumvent these issues in the vulnerable older adult.

A systematic review to summarize treatment patterns, guidelines, and characteristics of patients with renal cell carcinoma in the Asia-Pacific region.

INTRODUCTION: This systematic review evaluated treatment patterns and guidelines in advanced/metastatic and adjuvant renal cell carcinoma (RCC) in the Asia-Pacific region. AREAS COVERED: Embase, PubMed, and congresses were searched for observational studies and guidelines in accordance with PRISMA. Records published during 2016-2021 (2019-2021 for congresses) were included. EXPERT OPINION: Nine studies and three guidelines were identified overall. In advanced/metastatic RCC, the most common treatments were tyrosine kinase inhibitors (TKIs) (notably sunitinib: 33-100%) for first-line, and everolimus (13-85%) or axitinib (2-89%) for second-line therapy. In adjuvant RCC, sunitinib was most used (54%), followed by mammalian target of rapamycin inhibitors (mTORis, 27%) with immunotherapy being less common (16%). The guidelines provided varying recommendations for advanced/metastatic RCC. For first-line in advanced/metastatic clear cell RCC (the most common subtype), guidelines recommended mTORis (everolimus for poor-risk patients) (India, 2016); clinical study enrollment for high-risk patients or TKIs for low- to medium-risk patients (China, 2019); or immunotherapy based on survival benefits over sunitinib; dose adjustment was also recommended to manage TKI toxicities (Hong Kong, 2019). The landscape remained more static in the adjuvant setting, but best practice was uncertain. No clear trends were identified in patient characteristics.

External validation of the first prognostic nomogram for older adults with cancer.

Background: The geriatric oncology population tends to be complex because of multimorbidity, functional and cognitive decline, malnutrition and social frailty. Prognostic indices for predicting survival of elderly cancer patients to guide treatment remain scarce. A nomogram based on all domains of the geriatric assessment was previously developed at the National Cancer Centre Singapore (NCCS) to predict overall survival (OS) in elderly cancer patients. This nomogram comprised of six variables (age, eastern cooperative oncology group performance status, disease stage, geriatric depression scale (GDS), DETERMINE nutritional index and serum albumin). Objectives: To externally validate the NCCS prognostic nomogram. Design: This is a prospective cohort study. Methods: The nomogram was developed based on a training cohort of 249 patients aged ⩾70 years who attended the NCCS outpatient geriatric oncology clinic between May 2007 and November 2010. External validation of the nomogram using the Royston and Altman approach was carried out on an independent testing cohort of 252 patients from the same clinic between July 2015 and June 2017. Model misspecification, discrimination and calibration were assessed. Results: Median OS of the testing cohort was 3.1 years, which was significantly higher than the corresponding 1.0 year for the training cohort (log-rank p < 0.001). The nomogram achieved a high level of discrimination in the testing cohort (0.7112), comparable to the training cohort (0.7108). Predicted death probabilities were generally well calibrated with the observed death probabilities, as the joint test of calibration-in-the-large estimates at year 1, 2 and 3 from zeros and calibration slope from one was insignificant with p = 0.432. There were model misspecifications in GDS and serum albumin. Conclusion: This study externally validated the prognostic nomogram in an independent cohort of geriatric oncology patients. This supports the use of this nomogram in clinical practice.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.

AIM: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. METHODS: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. RESULTS: 455 patients were included (267 EGFR-mutated, EGFR-M+; 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. CONCLUSION: PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.

Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI. Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed. Results: Of 193 evaluable patients, 151 (78.2%) were T790M+ (T790M positive) with 96 (49.2%) tissue confirmed; 52% of patients received osimertinib in the second line setting. After median follow up of 37 months, median progression-free survival (PFS) of the entire cohort was 10.3 [95% confidence interval (CI): 8.64-11.50] months and median overall survival (OS) was 20 (95% CI: 15.61-23.13) months. Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs. 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs. 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs. 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027). Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need.

Clinical and Genomic Features of HER2 Exon 20 Insertion Mutations and Characterization of HER2 Expression by Immunohistochemistry in East Asian Non-Small-Cell Lung Cancer.

PURPOSE: HER2-altered non-small-cell lung cancer (NSCLC) represents a diverse subgroup, including mutations, amplifications, and overexpression. However, HER2 exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of HER2-altered NSCLC in an Asian tertiary cancer center. METHODS: We identified patients with HER2-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 (HER2)-mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. HER2 amplification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. RESULTS: Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of HER2 mutations was 3.1%-exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with HER2-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was HER2Y772_A775dup in 30 (75%), followed by HER2G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of HER2 exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature-similar to EGFR-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) HER2-mutated tumors resembled EGFR wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with HER2 RNA expression and HER2 amplification. CONCLUSION: The incidence of HER2 mutations is 3.1% in East Asian nonsquamous NSCLC. HER2 exon 20 insertion-mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) HER2 mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of HER2-mutated NSCLC warrant further investigation.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined. Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. Design, Setting, and Participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. Exposures: Adjuvant treatment was administered per investigator's discretion. Main Outcomes and Measures: The main outcome was 2-year disease-free survival (DFS). Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. Conclusions and Relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

PURPOSE: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M-negative resistance. EXPERIMENTAL DESIGN: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M-) disease. RESULTS: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M- tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. CONCLUSIONS: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Pilot Trial of a Combined Oncologist-Patient-Caregiver Communication Intervention in Singapore.

PURPOSE: High-quality end-of-life cancer care requires oncologists to communicate effectively and patients/caregivers to be participatory. However, most communication interventions target either but not both. We aimed to pilot a potentially disseminable combined oncologist-patient/caregiver intervention to improve oncologist empathic responses, discussions of prognosis and goals of care, and patient/caregiver participation. We assessed its feasibility, acceptability, and preliminary efficacy. METHODS: Between June 2018 and January 2019, we conducted a pilot 2-arm cluster trial in Singapore, randomly assigning 10 oncologists in a 1:1 ratio to receive the combined intervention or usual care. Intervention arm oncologists received online communication skills training, and their patients received a brief prompt sheet before consultations. We audio recorded consultations with 60 patients with stage IV solid malignancy and analyzed 30 in the postintervention phase. The study was not powered for statistical significance. RESULTS: Participation rates for oncologists and patients were 100% and 63%, respectively. All oncologists completed the online training within an average of 4.5 weeks; 73% of the patients selected at least 1 question in the prompt sheet. Compared with the control arm, intervention arm oncologists had more empathic responses in total (relative risk [RR], 1.66) and for every patient/caregiver negative emotion (RR, 2.01). Their consultations were more likely to involve discussions of prognosis (RR, 3.00) and goals of care, and their patients were more likely to ask a prognosis-related question (RR, 2.00; P > .05 for all). CONCLUSION: The combined oncologist-patient/caregiver intervention is feasible and acceptable and has the potential to improve communication within consultations.

Real-world outcome with abiraterone acetate plus prednisone in Asian men with metastatic castrate-resistant prostate cancer: The Singapore experience.

INTRODUCTION: Several small studies have reviewed the efficacy of abiraterone acetate plus prednisolone (AAP) in clinical practice outside a trial setting. We report the largest cohort study of clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with AAP in a multicenter multiracial clinical setting. METHODS: A retrospective analysis on mCRPC patients treated at four tertiary hospitals in Singapore from 2012 to 2017 was conducted. Disease characteristics, treatment outcomes, and adverse events were retrieved from electronic medical records. Primary clinical end-point was overall survival (OS). A subset analysis of patients with various variables and OS curves were generated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Out of 200 patients with mCRPC treated with AAP, 163 (81.5%) patients were chemo-naïve (CN) and 37 (18.5%) patients were postchemotherapy (PC), with the median age of 68 (34-87) and 65 (52-80) years, respectively. Median OS was 20.0 (95% CI, 18.3-22.9) and 10.5 months (95% CI, 1.1-40.5) for CN and PC cohorts, respectively. A subset analysis of 108 patients showed a significantly longer OS in patients who had prior ADT for more than 12 months in CN patients (P < 0.001). Incidences of G3/G4 events were around 6.6%; most common side effect being hypertension with an incidence of 2.4%. CONCLUSIONS: Treatment of CN and PC patients with AAP was associated with a comparable OS and progression-free survival to the reported series. Patients who were responsive to prior ADT of 12 months or more were associated with an improved OS.

Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.

INTRODUCTION: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes. METHODS: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected. RESULTS: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009). CONCLUSIONS: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

OBJECTIVES: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. MATERIALS AND METHODS: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. RESULTS: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. CONCLUSIONS: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

PURPOSE: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC. PATIENTS AND METHODS: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG. RESULTS: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154). CONCLUSION: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.

Metronomic chemotherapy: A relook at its basis and rationale.

Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema.

Comprehensive Geriatric Assessment (CGA) based risk factors for increased caregiver burden among elderly Asian patients with cancer.

OBJECTIVE: This study aims to identify Comprehensive Geriatric Assessment (CGA) based risk factors to help predict caregiver burden among elderly patients with cancer. MATERIALS AND METHOD: The study evaluated 249 patients newly diagnosed with cancer, aged 70years and above, who attended the geriatric oncology clinic at the National Cancer Centre Singapore between 2007 and 2010. RESULTS: Out of 249 patients, 244 patients had information available on family caregiver burden and were analysed. On univariate analysis, ADL dependence, lower IADL scores, ECOG performance status of 3-4, higher fall risk, lower scores in dominant hand grip strength test and mini mental state examination, polypharmacy, higher nutritional risk, haemoglobin <12g/dL and presence of geriatric syndromes were significantly associated with mild to severe caregiver burden. On multivariate analysis, only ECOG performance status of 3-4 (odds ratio [OR], 4.47; 95% confidence interval [CI], 2.27-8.80) and haemoglobin <12g/dL (OR, 2.38; 95% CI, 1.14-4.99) were associated with an increased probability of mild to severe caregiver burden. The model achieved a good fit (Hosmer-Lemeshow's p=0.196) and discrimination (area under the curve [AUC]=0.742; bias-corrected AUC=0.737). Based on this, patients were stratified into 3 risk groups with different proportion of patients with increased caregiver burden (low risk: 3.9% vs intermediate risk: 18.8% vs high risk: 39.6%; p<0.001). CONCLUSION: ECOG performance status and haemoglobin were associated with increased caregiver burden among elderly patients with cancer. Using these two factors in the clinic may help clinicians identify caregivers at risk and take preventive action to mitigate that.

Identification of Comprehensive Geriatric Assessment Based Risk Factors for Malnutrition in Elderly Asian Cancer Patients.

PURPOSE: Elderly cancer patients are at increased risk for malnutrition. We aim to identify comprehensive geriatric assessment (CGA) based clinical factors associated with increased nutritional risk and develop a clinical scoring system to identify nutritional risk in elderly cancer patients. PATIENTS AND METHODS: CGA data was collected from 249 Asian patients aged 70 years or older. Nutritional risk was assessed based on the Nutrition Screening Initiative (NSI) checklist. Univariate and multivariate logistic regression analyses were applied to assess the association between patient clinical factors together with domains within the CGA and moderate to high nutritional risk. Goodness of fit was assessed using Hosmer-Lemeshow test. Discrimination ability was assessed based on the area under the receiver operating characteristics curve (AUC). Internal validation was performed using simulated datasets via bootstrapping. RESULTS: Among the 249 patients, 184 (74%) had moderate to high nutritional risk. Multivariate logistic regression analysis identified stage 3-4 disease (Odds Ratio [OR] 2.54; 95% CI, 1.14-5.69), ECOG performance status of 2-4 (OR 3.04; 95% CI, 1.57-5.88), presence of depression (OR 5.99; 95% CI, 1.99-18.02) and haemoglobin levels <12 g/dL (OR 3.00; 95% CI 1.54-5.84) as significant independent factors associated with moderate to high nutritional risk. The model achieved good calibration (Hosmer-Lemeshow test's p = 0.17) and discrimination (AUC = 0.80). It retained good calibration and discrimination (bias-corrected AUC = 0.79) under internal validation. CONCLUSION: Having advanced stage of cancer, poor performance status, depression and anaemia were found to be predictors of moderate to high nutritional risk. Early identification of patients with these risk factors will allow for nutritional interventions that may improve treatment tolerance, quality of life and survival outcomes.