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Background: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib., Methods: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events., Results: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%)., Conclusion: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted., (© 2024. The Author(s).)

Scirrhous hepatocellular carcinoma (S-HCC) represents an uncommon subtype of HCC. During radiological evaluation this unique subtype is frequently mistaken as cholangiocarcinoma, fibrolamellar HCC, or metastatic adenocarcinoma. Here, we present the case of a 50-year-old woman with a large hepatic mass. A triple-phase computed tomography of the liver revealed an arterial enhancing lesion without portovenous washout at hepatic segment 4a/8. The liver biopsy showed hepatocellular characteristics and was positive for Hep Par 1, CK7, CK19, Arginase 1 and CEA, indicating atypical S-HCC. This patient had achieved tumor control with combined treatment with atezolizumab plus bevacizumab and was then treated with lenvatinib after tumor progression. The patient died 15 months after the initial diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Archwamety, Kunapinun, Sirinvaravong, Apisarnthanarak, Akewanlop and Korphaisarn.)

This study conducted a cost-utility analysis and a budget impact analysis (BIA) of outpatient oral chemotherapy versus inpatient intravenous chemotherapy for stage III colorectal cancer (CRC) in Thailand. A Markov model was constructed to estimate the lifetime cost and health outcomes based on a societal perspective. Eight chemotherapy strategies were compared. Clinical and cost data on adjuvant chemotherapy were collected from the medical records of 1747 patients at Siriraj Hospital, Thailand. The cost-effectiveness results were interpreted against a Thai willingness-to-pay threshold of USD 5003/quality-adjusted life year (QALY) gained. A 5-year BIA was performed. Of the eight strategies, CAPOX then FOLFIRI yielded the highest life-year and QALY gains. Its total lifetime cost was also the highest. An incremental cost-effectiveness ratio of CAPOX then FOLFIRI compared to 5FU/LV then FOLFOX, a commonly used regimen USD was 4258 per QALY gained.The BIA showed that when generic drug prices were applied, 5-FU/LV then FOLFOX had the smallest budgetary impact (USD 9.1 million). CAPOX then FOLFIRI required an approximately three times higher budgetary level (USD 25.1 million). CAPOX then FOLFIRI is the best option. It is cost-effective compared with 5-FU/LV then FOLFOX. However, policymakers should consider the relatively high budgetary burden of the CAPOX then FOLFIRI regimen.

Purpose: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data., Methods: Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points., Results: At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis., Conclusion: These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

Here, we report a case of metastatic Epstein-Barr virus (EBV)-related primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) in a young, nonsmoking female who responded well to treatment with two types of immune checkpoint inhibitors (ICIs). This is the first case report of a favorable outcome to ICIs in the late-line treatment of advanced PPLELC patients with programmed cell death-ligand 1 (PD-L1) expression., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA., Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual., Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively., Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204., (©2022 The Authors; Published by the American Association for Cancer Research.)

Aim: To investigate the clinicopathological factors, molecular features, and prognostic implications associated with loss of Caudal-related homeobox transcription factor 2 (CDX-2) expression in colorectal cancer (CRC) patients., Methods: Immunohistochemistry for CDX-2 expression was performed on formalin-fixed, paraffin-embedded primary CRC tissue samples from 449 patients. Correlation between CDX-2 expression and clinicopathological and molecular characteristics was evaluated. Univariate and multivariate survival analyses were performed to determine the prognostic value of loss of CDX-2 expression., Results: Of 449 patients, 84% were stage I-III. CDX-2-negative expression was identified in 18 of 441 (4.1%) patients. Loss of CDX-2 expression was more commonly found in patients with right-sided tumors rather than left-sided tumors (odds ratio [OR] = 3.57; p = 0.009), deficient mismatch repair (dMMR) compared to proficient MMR (pMMR) (OR = 3.7; p = 0.012), and BRAF mutation compared to BRAF wild type (OR = 8.06; p = 0.002). Univariate analysis revealed that stage I-III CRC patients with loss of CDX-2 expression had significantly worse overall survival (OS) and disease-free survival (DFS) than those with positive CDX-2 expression (5-year OS = 33.3% vs. 74.6%, respectively; p < 0.001, and 5-year DFS: 42.9% vs. 69.5%, respectively; p = 0.004). Loss of CDX-2 expression remained significantly associated with worse OS compared to positive CDX-2 expression in multivariate analysis (hazard ratio [HR] = 2.4; 95% confidence interval [CI], 1.12-5.11; p = 0.023)., Conclusions: Loss of CDX-2 expression was found to be associated with right-sided tumor, dMMR status, and BRAF mutation. Moreover, loss of CDX-2 expression is a poor prognostic factor for OS in stage I-III, even among patients with dMMR tumors., (© 2021 John Wiley & Sons Australia, Ltd.)

Introduction: Adjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA., Methods: Patients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB-IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage., Results: Overall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10-0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13-0.40), regardless of disease stage., Conclusions: These findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR Ab) as first-line treatment only in patients with left-sided RAS wild type (RASwt ) metastatic colorectal cancer (mCRC). However, there are no guideline recommendations specific to tumor sidedness in subsequent-line treatment. This study aimed to investigate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC., Methods: Medical records of patients diagnosed with mCRC at 3 academic centers in Thailand (Siriraj, Chulalongkorn, and Ramathibodi hospital) between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt mCRC who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using Kaplan-Meier method, and those results were compared using log-rank test., Results: Among the 2,102 patients who had KRAS analysis data, 1,130 (54%) patients had KRASwt . Of those, 413 patients received anti-EGFR Ab in second- or later-line treatment. One hundred and sixty-two of 413 (39%) patients had extended RAS analysis. Seventy (17%) patients had right-sided tumors. Two hundred and thirty-eight (58%) patients received anti-EGFR Ab in the third line, and 132 (32%) patients and 43 (10%) patients were treated in the second and more than third line, respectively. Single-agent irinotecan was the most commonly used backbone chemotherapy (303/413, 73%). Patients with right-sided tumors had non-significantly inferior PFS compared to patients with left-sided tumors (median PFS: 5.7 months (mo), 95% confidence interval [CI]: 3.9-7.5 vs. 7.5 mo, 95% CI 6.5-8.5; p=0.17). Subgroup analysis showed no difference in PFS when stratified by treatment lines. Patient with right-sided tumors had significantly inferior OS compared to patients with left-sided tumors (median OS: 23.3 mo vs. 29.9 mo; p=0.005)., Conclusions: To date, this is the largest real world data of the effect of primary tumor location on anti-EGFR Ab which demonstrated that tumor sidedness has no significant impact on treatment outcomes in KRASwt mCRC patients receiving second- or later-line therapy. Our findings do not support the utility of tumor sidedness for treatment selection in these settings. We confirmed that patients with right-sided tumors had significantly worse survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Archwamety, Teeyapun, Siripoon, Poungvarin, Tanasanvimon, Sirachainan, Akewanlop and Korphaisarn.)

Background: Low muscle mass is associated with worse cancer treatment outcomes. Although dual-energy X-ray absorptiometry or computerized tomography-based analysis have both been widely studied in this clinical setting, studies in the use of bioelectrical impedance analysis (BIA) remain limited. The aim of this prospective study was to investigate for association between body composition estimated by BIA and hematologic adverse events in early-stage breast cancer patients receiving chemotherapy. Methods: A total of 144 female patients were enrolled. Before the first cycle of chemotherapy, body weight and fat-free mass were measured by a BIA device and then those values were converted into body mass index and fat-free mass index. Association between fat-free mass index and composite adverse events (CAEs), including grade 4 neutropenia, febrile neutropenia, or relative dose intensity <85%, was explored. Results: CAEs occurred in 85 patients (59%), and point biserial correlation showed an inverse correlation between the fat-free mass index and CAE. No included patients were sarcopenic (fat-free mass index <11.4 kg/m 2 ). Receiver operating characteristic curve analysis revealed <14.85 kg/m 2 as the cutoff value indicating a low fat-free mass index. Using this cutoff, 85 patients were classified as having a low fat-free mass index, and 62 of those patients (72.9%) had CAE (relative risk: 1.86, P  < .001). After adjusting for other factors, a low fat-free mass index was found to be independently associated with a high CAE (adjusted odds ratio: 4.562, 95% CI: 2.162-9.627, P  < .001). Conclusion: Low fat-free mass index is an independent predictor of increased risk of hematologic adverse events in early-stage breast cancer patients receiving chemotherapy. Estimation of fat-free mass index by BIA may identify at-risk patients so that interventions can be considered to improve treatment outcomes.

Here, we summarize the initial results from the ADAURA clinical study looking at treatment with osimertinib in patients with a specific type of non-small cell lung cancer (also called NSCLC). Osimertinib (TAGRISSO®) is a medication used to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for 'epidermal growth factor receptor'. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. ClinicalTrials.gov NCT number: NCT02511106.

Purpose: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinicopathological characteristics and outcome of adolescent and young adult (AYA)-onset sporadic CRC patients. Methods: Medical records of patients who were diagnosed adenocarcinoma of colon or rectum at Siriraj Hospital between 2007 and 2018 were retrospectively reviewed. The patients were classified into two groups: AYA-onset CRC (age 15-39 years) and adult-onset CRC (age >50 years). Associations between sporadic microsatellite stable (MSS) AYA-/adult-onset CRC and clinicopathological features and outcome were evaluated. Results: A total of 203 patients were diagnosed with AYA-onset CRC with no known history of familial CRC syndromes, 119 had data on mismatch repair status; 98 confirmed MSS CRC. AYA-onset CRC patients were commonly found with left-sided rather than right-sided tumors (77.1% vs. 22%) and late stage of disease (80.7% in stage III-IV vs. 19.3% in stage I-II). Compared with adult-onset CRC (218 patients), AYA-onset MSS CRC had more patients with female gender ( p  = 0.038), perineural invasion ( p  = 0.003), and signet ring cell/mucinous histology ( p  = 0.132). On univariate analysis, male gender and mucinous/signet ring cell histology had worse overall survival (OS) ( p  = 0.004 and p  = 0.072, respectively) and remained significant in multivariate analysis for signet ring cell histology ( p  = 0.008). There was no difference in disease-free survival and OS between both age groups. Conclusion: Sporadic MSS AYA-onset CRC patients were associated with female gender and aggressive pathological characteristics. However, there was no difference in survival outcome between AYA-onset and adult-onset groups.

Background: Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity., Methods: HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy., Results: Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (r b  = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks., Conclusion: The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy., Competing Interests: Declaration of competing interest HS Rugo has received travel, accommodations, and expenses from Amgen, Merck, Viatris Inc, Pfizer, and Puma Biotechnology and research funding (provided to the Regents of the University of California) from Eisai, Genentech/Roche, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Daiichi, Immunomedics, and Pfizer. EJ Pennella was a paid employee of Mylan Inc (now Viatris Inc) during the time of the study and may hold stock with the company. U Gopalakrishnan, HF Koch, and A Barve are paid employees of Viatris Inc and may hold stock with the company. M Hernandez-Bronchud has served as a consultant/advisory board member for Viatris Inc. S Loganathan, S Deodhar, and A Marwah are paid employees of Biocon Research Ltd and may hold stock with the company. C Akewanlop has received travel, accommodations, and expenses from Amgen, AstraZeneca, Roche, and Bristol-Myers Squibb. CF Waller is a consultant/advisory board member for Viatris Inc. J Herson, A Manikhas, JD Parra, MLT Abesamis-Tiambeng, I Vynnychenko, I Bondarenko, V Sriuranpong, S Roy, and EP Yanez Ruiz have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE., Methods: HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient., Results: At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan-Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up., Conclusion: This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015.

Background: Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor ( EGFR ) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown., Methods: In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety., Results: A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted., Conclusions: In patients with stage IB to IIIA EGFR mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: Obesity is increasing worldwide. Previous studies of the impact of obesity on breast cancer outcomes have reported conflicting results. We investigated the association of obesity and breast cancer survival in Thai patients., Methods: Medical records of operable breast cancer patients diagnosed and treated at Siriraj Hospital between January 2004 and December 2011 were reviewed. Demographic data, tumor characteristics, stage, treatment and adverse event were described. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2 using Asian's cutoff value.  Survivals in both obese and non-obese patient groups were analyzed., Results: A total of 400 patients were included, 200 in each group. Obese patients were older and associated with more comorbidity. Obesity was associated with larger tumor size (p = 0.011), greater numbers of lymph node involvement (p = 0.003) and more advanced stage (p = 0.01). Obese patients were more likely to receive less adjuvant chemotherapy and hormonal treatment. There was no statistically significant difference in disease-free survival (DFS) (Hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.46 to 1.13) and overall survival (OS) (HR 0.77, 95% CI 0.43 to 1.39) between obese and non-obese patients. Interestingly, obesity was associated with fewer complications from chemotherapy than non-obese patients (p = 0.047)., Conclusion: Obesity had no adverse prognostic impact association on both DFS and OS in Thai patients with operable breast cancer, although obese patients more often presented with larger tumor and higher numbers of lymph node involvement., .

Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy., Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer., Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred., Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane., Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events., Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%)., Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome., Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.

Aim: To determine the prognostic significance of deficient mismatch repair (dMMR) and BRAF V600E in Thai sporadic colorectal cancer (CRC) patients., Methods: We studied a total of 211 out of 405 specimens obtained from newly diagnosed CRC patients between October 1, 2006 and December 31, 2007 at Siriraj Hospital, Mahidol University. Formalin-fixed paraffin-embedded blocks of CRC tissue samples were analyzed for dMMR by detection of MMR protein expression loss by immunohistochemistry or microsatellite instability using polymerase chain reaction (PCR)-DHPLC. BRAF V600E mutational analysis was performed in DNA extracted from the same archival tissues by two-round allele-specific PCR and analyzed by high sensitivity DHPLC. Associations between patient characteristics, MMR and BRAF status with disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier survival plots and log-rank test together with Cox's proportional hazard regression., Results: dMMR and BRAF V600E mutations were identified in 31 of 208 (14.9%) and 23 of 211 (10.9%) tumors, respectively. dMMR was more commonly found in patients with primary colon tumors rather than rectal cancer (20.4% vs 7.6%, P =0.01), but there was no difference in MMR status between the right-sided and left-sided colon tumors (20.8% vs 34.6%, P = 0.24). dMMR was associated with early-stage rather than metastatic disease (17.3% vs 0%, P = 0.015). No clinicopathological features such primary site or tumor differentiation were associated with the BRAF mutation. Six of 31 (19.3%) samples with dMMR carried the BRAF mutation, while 17 of 177 (9.6%) with proficient MMR (pMMR) harbored the mutation (P = 0.11). Notably, patients with dMMR tumors had significantly superior DFS (HR = 0.30, 95%CI: 0.15-0.77; P = 0.01) and OS (HR = 0.29, 95%CI: 0.10-0.84; P = 0.02) compared with patients with pMMR tumors. By contrast, the BRAF V600E mutation had no prognostic impact on DFS and OS., Conclusion: The prevalence of dMMR and BRAF V600E in Thai sporadic CRC patients was 15% and 11%, respectively. The dMMR phenotype was associated with a favorable outcome.

Objective: Although anthracycline-based regimen is standard neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC), there is some concern over its toxicities such as alopecia and cardiotoxicity. Gemcitabine is another active agent in metastatic breast cancer after failure to anthracycline with less toxicity. The objective of the present study is to evaluate the efficacy and safety of the combination of gemcitabine and carboplatin as NAC in LABC., Material and Method: Patients with histologically confirmed LABC (T3, T4 or N2 and M0) were included. Patients were scheduled to receive 3 cycles of neoadjuvant GC (gemcitabine 1,000 mg/m2 D1, D8 and carboplatin AUC x 5 D1) every 21 days. Patients with clinical response underwent surgery and additional 3 cycles of adjuvant GC. Primary endpoint was clinical response rate whereas secondary endpoints included pathological response, DFS, OS and toxicity., Results: Between 2004 and 2007, 40 LABC patients were enrolled. Of 40 patients, 35 were evaluable for efficacy and 40 for toxicity. Twenty-three out of 35 patients (65%) obtained cPR. Among 22 patients who had clinical response and who underwent surgery, overall pathological response rate was 51.5% with 1-pCR (2.9%) and 17-pPR (48.5%). All 7 triple-negative patients had pathological response (1-pCR, 6-pPR). At median follow-up of 59 months, median DFS and OS were not reached. Five-year OS and DFS were 67% and 62%, respectively Major adverse effect was myelosuppression without fatal complications., Conclusion: The combination GC was feasible and well-tolerated for LABC in neoadjuvant setting. Triple-negative subgroup seems to have high response to GC.

A 52-year-old man suffered from visual disturbance for 5 months. He then developed malaise, constipation and anorexia with significant weight loss. Physical examination showed noticeable signs of hypothyroidism, such as slurred speech, dry skin, macroglossia, myoedema and slow relaxation of ankle reflexes. In addition, eye exam showed abnormal visual acuity with left homonymous hemianopia. A large mass was found at right scapular region. Endocrinologic investigation results were compatible with secondary hypothyroidism with adrenal insufficiency. Subsequent CT brain revealed an enhancing mass at pituitary gland and also a mass at right occipital lobe with surrounding edema. CT of chest demonstrated multiple lung nodules, right scapular mass and incidentally revealed 8.7-cm hypervascular mass at left kidney. The final diagnosis was renal cell carcinoma with bone, lung, brain and pituitary metastasis. He received hormone replacement therapy as well as bisphosphonate and brain radiation. Following treatments, he was able to return to work with recovery of visual impairment. Pituitary metastasis is a rare condition. Our patient presented with symptoms of hypothyroidism which may mimic pituitary adenoma, but had other clues of malignancy such as significant weight loss and scapular mass. The most common cancers that occasionally metastasize to pituitary gland are breast and lung cancer. Previously, renal cell carcinoma with pituitary metastasis has been reported. Unlike ourpatient, most of these cases developed metachronous pituitary metastasis.

Purposes: Ondansetron plus dexamethasone are standard antiemetic agents for highly emetogenic chemotherapy. Metoclopramide is a dopamine antagonist, which may enhance efficacy of ondansetron and dexamethasone. The objective of this study was to assess the efficacy and tolerability of metoclopramide added to standard antiemetic regimen for prophylaxis of cisplatin-induced emesis., Methods: Patients who received ≥50 mg/m(2) of cisplatin for the first time were given intravenous ondansetron and dexamethasone on day 1 and were randomized to receive either standard antiemetics (ondansetron 8 mg orally bid on days 2-5 and dexamethasone 8 mg orally bid on days 2-4) plus metoclopramide 20 mg orally qid on days 2-5 or a placebo. The primary endpoint was a complete response (CR) rate defined as no emesis and no rescue treatment over a 120-h period. Secondary endpoints included severity of nausea and vomiting, time to first emesis, quality of life, and adverse effects., Results: Among 162 patients, 50 patients (60%) in the metoclopramide group and 42 patients (53%) in the control group achieved CR (p = 0.36). The mean times to first emesis in the metoclopramide and control groups were 88 and 75 h, respectively (p = 0.18). The degrees of nausea and vomiting in both groups were similar. Eleven patients (13%) in the metoclopramide group and 20 (25%) in the control group required rescue treatment (p = 0.05). Quality of life and adverse effects were not different between the two groups., Conclusion: The addition of metoclopramide to ondansetron plus dexamethasone reduced the use of rescue medication, but did not affect complete response rate, quality of life or adverse effects.

Objective: The aim of the present prospective study was to evaluate the correlation between the change of serum c-reactive protein (CRP) levels and response to chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer., Material and Method: Patients with locally advanced or metastatic non-small cell lung cancer who received the first line chemotherapy were measured serum CRP levels prior to treatment. Chemotherapy regimen was given to patients according to physicians and radiologic imaging was evaluated after two or three cycles of treatment. Serum CRP levels were measured first time at pre-treatment and second time in patients who had pre-treatment serum CRP levels greater than normal range (3 mg/l) at the time of response assessment or clinical progression. The primary endpoint was the correlation between change of serum CRP levels and radiologic response. The secondary endpoint was the prevalence of elevated CRP levels in advanced NSCLC patients and correlation between initial CRP levels and progression free survival (PFS)., Results: Fifty four patients were enrolled. Prevalence of elevated CRP levels in advanced NSCLC was 76%. Thirty patients had serial serum CRP measured. There was correlation between change in serum CRP levels and response to treatment (r = 0.43, p = 0.018, spearman rank). There was significant correlation between response to treatment and decrease in CRP levels greater than 50% (p = 0.009, Fisher's exact test). In contrast there was no correlation between progression and increase in CRP levels (p = 0.640, Fisher's exact test). All patients with serial CRP levels decreased to normal range (< 3 mg/ l) had response to chemotherapy. High pre-treatment CRP levels (> 100 mg/l) correlated with poor PFS. Median PFS for patients with pre-treatment CRP levels of 3-30 mg/l, 30-100 mg/l and >100 mg/l was 23.0 weeks, 13.0 weeks and 6.3 weeks, respectively. Patients with serial CRP levels less than 3 mg/l had greater PFS than patients with serial CRP levels higher than 3 mg/l (p = 0.026, log rank test)., Conclusion: The present study suggested that high levels of pre-treatment serum CRP and persistent CRP in serum was a poor prognostic factor. The decrease in CRP levels greater than 50% was a simple method to predict the response to treatment in patients with locally advanced or metastatic non-small lung cancer.

Background: Colorectal cancer is the third most common cancer worldwide. There were only a few reports of disease outcomes in Thai. Therefore, the authors retrospectively reviewed the clinical characteristics and disease outcome of patients with curable colorectal cancer treated at Siriraj Hospital, the largest tertiary-care hospital in Thailand., Material and Method: Medical records of colorectal cancer patients diagnosed at Siriraj Hospital between January 2003 and December 2007 were reviewed. The records of the patients presenting with stage I-III and had been follow-up for at least 2 years were explored. Clinical characteristics, including demographic data, primary tumor site, TMN staging, histopathology, and CEA level were described. Disease outcome including survival, recurrence of disease and complication were analyzed., Results: One thousand forty-seven colorectal cancer patients were diagnosed and completely staged during the study period. The incidence of stage I-IV was 9%, 22%, 37% and 32%, respectively. Three hundred fifty-five patients with stage I-III colorectal cancer were analyzed. The ratio of male and female was 1.4:1. The median age was 59.8 years. Forty-eight percent and 52% of patients had colon and rectal cancer, respectively. The median follow-up time was 63.3 months. The mean time from diagnosis to surgery was 23 days. Two hundred forty eight patients (70%) received adjuvant or neoadjuvant chemotherapy with the majority receiving 5-fluorouracil and leucovorin. 5-year disease free survival rate in stage I-III was 90%, 85% and 58%, respectively and 5-year overall survival in stage I-III was 93%, 93% and 73%, respectively. Independent risk factors for disease-free survival were gender preoperative CEA and stage; for overall survival were gender and stage., Conclusion: Approximately two-thirds (68%) of patients with colorectal cancer at Siriraj hospital presented with a potentially curable stage. Multi-modality treatments with surgery, adjuvant chemotherapy and radiation resulted in comparable survival as in Western countries. Independent risk factors for worse survival in this cohort were stage III disease and male gender.

Expression of estrogen-receptor (ER), progesterone-receptor (PR) and HER-2 has recently been linked with various breast cancer subtypes identified by gene microarray. This study aimed to document breast cancer subtypes based on ER, PR and HER-2 status in Thai women, where expression of these subtypes may not be similar to those evident in Western women. During 2009 to 2010, histological findings from 324 invasive ductal carcinomas (IDC) at Siriraj Hospital were studied. Various subtypes of IDC were identified according to expression of ER, PR and HER-2: luminal-A (ER+;PR+/-;HER-2-), luminal-B (ER+;PR+/-;HER-2+), HER-2 (ER-;PR- ;HER-2+) and basal-like (ER-;PR-;HER-2-). As well, associations of tumor size, tumor grade, nodal status, angiolymphatic invasion (ALI), multicentricity and multifocality with different breast cancer subtypes were studied. Of 324 IDCs, 143 (44.1%), 147 (45.4%), 15 (4.6%) and 12 (3.7%) were T1, T2, T3 and T4, respectively. Most tumors were grade 2 (54.9%) and had no nodal involvement (53.4%). According to ER, PR and HER-2 status, 192 (59.3%), 40 (12.3%), 43 (13.3%) and 49 (15.1%) tumors were luminal-A, luminal-B, HER-2 and basal-like subtypes. HER-2 subtype presented with large tumor (p=0.04, ANOVA). Luminal-A IDC was associated with single foci (p<0.01, χ2). HER-2 and basal-like subtypes were likely to have high tumor grade (p<0.01, χ2). In addition, HER-2 subtype had higher number of nodal involvement (p=0.048, χ2). In conclusion, the luminal-A subtype accounted for the majority of IDCs in Thai women. Percentages of HER-2 and basal-like IDCs were high, compared with a recent study from the USA. The HER-2 subtype was related with high nodal invasion. The findings may highlight biological differences between IDCs occurring in Asian and Western women.

Human epithelial mucin, MUC-1, is commonly expressed in adenocarcinoma including 80% of breast cancers. erbB-2 is overexpressed in approximately 30% of breast cancers. Expression of MUC-1 and erbB-2 may be partially overlapping but discoordinate. Therefore, combined use of antibodies directed against these two antigens might increase the number of patients who benefit from immunotherapy. Monoclonal antibody (MAb) DF3 recognizes the MUC-1 tandem repeat. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by monocyte-derived macrophages mediated by MAb DF3 and its bispecific antibody (BsAb) DF3xH22 with the second epitope directed against the Fc component of phagocytic cells. Purified monocytes from healthy donors were cultured with granulocyte macrophage colony-stimulating factor with or without IFN-gamma. antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) assays were performed with these macrophages and MUC-1-expressing target cells (ZR75-1) in the presence of MAb DF3 and BsAb DF3xH22. ADCP was measured by two-color fluorescence flow cytometry using PKH2 (green fluorescent dye) and R-phytoerythrin (RPE) (red)-conjugated MAb against human CD14 and CD11b and was confirmed by confocal microscopy. ADCC was measured by (51)Cr release assay. Immunohistochemical staining studies of MUC-1 and erbB-2 were performed on 67 primary breast cancer tissues. Expression of MUC-1 and erbB-2 was partially overlapping but discoordinate in 67 consecutive breast cancers. Both MAb DF3 and BsAb DF3xH22 mediated ADCP. However, ADCP mediated by MAb DF3 was greater than that mediated by BsAb DF3xH22. ADCC as detected by (51)Cr release was not seen with either antibody. The addition of IFN-gamma to monocyte-derived macrophage cultures inhibited ADCP compared to granulocyte macrophage colony-stimulating factor alone. Given the partially overlapping but discoordinate expression of MUC-1 and erbB-2 in breast cancer, therapy directed toward both antigens should be considered. MAb DF3 and the BsAb DF3xH22, can effectively mediate phagocytosis of MUC-1-expressing target cells. Further investigations are needed to determine whether this antibody-induced phagocytosis results in long-term specific T-cell activation against MUC-1.