Comparative effectiveness analysis of survival with first-line palbociclib or ribociclib plus AI in HR + /HER2- advanced breast cancer (CEPRA study): preliminary analysis of real-world data from Thailand.

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.

Immunotherapy and Biomarkers in Sarcoma.

OPINION STATEMENT: Sarcoma describes a rare and heterogeneous group of diseases. Current treatment options for metastatic sarcoma are quite limited. Conventional treatments with chemotherapy or anti-angiogenic agents result in a non-durable response and a survival rate of approximately 12 to 18 months. In addition, the benefits of such treatments remain limited in some sarcoma subtypes only. Immunotherapy is an emerging treatment for several cancer types with promising outcomes. Studies at the cellular level have shown a relatively high immunogenicity in some subtypes of sarcoma. It is therefore hypothesized that sarcoma may respond to immunotherapy. However, sarcoma is a heterogeneous disease and differences in terms of immunogenicity exist. A multitude of immune-based treatment approaches for sarcoma have been explored. This includes immune checkpoint inhibitors, therapeutic vaccines, and adoptive cell therapy. Single-agent immunotherapy has exhibited efficacy against some sarcoma subtypes, including alveolar soft-part sarcoma, angiosarcoma, and undifferentiated pleomorphic sarcoma. Combination immunotherapy appears superior to single-agent immunotherapy in terms of response, and several ongoing studies of immunotherapy using single/combination immune checkpoint inhibitors and combination with anti-angiogenesis have begun to report beneficial results. Predictive and prognostic biomarkers are also under active investigations, with particular interest in tumor-infiltrating lymphocytes or high tumor mutational burden levels. However, the information is still limited and further studies are needed.

Incidence and Prognostic Values in Human Epidermal Growth Factor Receptor 2-Low Expression Metastatic Breast Cancer in Southeast Asian Population: A 10-Year Retrospective Study.

PURPOSE: Breast cancer progression varies across molecular subtypes, and treatment options for human epidermal growth factor receptor 2 (HER2)-low expression tumors are limited compared with those of HER2 overexpression tumors. Comprehensive information regarding the epidemiology and clinical outcomes of metastatic HER2-low expression breast cancer in a Southeast Asian population is lacking. METHODS: This retrospective cohort study was performed to analyze data from patients with de novo advanced breast cancer, including HER2 expression, tumor stage, and metastatic pattern. Statistical analyses, including chi-square tests and survival analyses, were used to compare HER2-low expression and HER2-negative groups. RESULTS: Of the 491 patients, 21.2% had HER2-low expression, 30% had HER2 overexpression, and 50% had HER2-negative expression. Among the hormone receptor (HR)-positive patients, 34% had HER2-low expression; in the triple-negative patients, the HER2-low incidence was 20.6%. No significant differences in clinical characteristics between HER2-low and HER2-negative groups were observed, except for more HR-positive patients in the HER2-low group. HER2-low patients had a longer overall survival (OS) than HER2-negative patients (43 v 23 months; hazard ratio, 0.7; P < .001), especially in HR-positive patients. After adjusting for HR status, HER2-low patients maintained improved outcomes. HR-positive HER2-low patients showed nonsignificant OS gains compared with HR-positive HER2-negative patients, regardless of first-line chemotherapy or endocrine therapy. CONCLUSION: This study revealed the incidence and clinical outcomes of HER2-low expression in de novo advanced breast cancer, suggesting favorable outcomes, particularly in HR-positive breast cancer. These findings may inform personalized treatment strategies. Further research into the mechanisms and implications of HER2-low expression in breast cancer is required.

Cost-utility and budget impact analysis of neoadjuvant dual HER2 targeted therapy for HER2-positive breast cancer in Sri Lanka.

This study aimed to assess the cost-utility and budget impact of dual to single HER2 targeted neoadjuvant therapy for HER2-positive breast cancer in Sri Lanka. A five-health state Markov model with lifetime horizon was used to assess the cost-utility of neoadjuvant trastuzumab (T) plus pertuzumab (P) or lapatinib (L) compared to single therapy of T with chemotherapy (C), in public healthcare system and societal perspectives. Input parameters were estimated using local data, network meta-analysis, published reports and literature. Costs were adjusted to year 2021 (1USD = LKR194.78). Five-year budget impact for public healthcare system was assessed. Incremental cost-effectiveness ratios in societal perspective for neoadjuvantLTC plus adjuvantT (strategy 3), neoadjuvantPTC plus adjuvantT (strategy 2), neoadjuvantLTC plus adjuvantLT (strategy 5), and neoadjuvantPTC plus adjuvantPT (strategy 4) compared to neoadjuvantTC plus adjuvantT (strategy 1) were USD2716, USD5600, USD6878, and USD12127 per QALY gained, respectively. One GDP per-capita (USD3815) was considered as the cost-effectiveness threshold for the analysis. Even though only the ICER for strategy 3 was cost-effective, uncertainty of efficacy parameter was revealed. For strategy 2 neoadjuvant PTC plus adjuvant T, a 25% reduction of neoadjuvant regimen cost was required to be cost effective for use in early HER2 positive breast cancer.

Clinical Treatment Score Post-5 Years as a Tool for Risk Estimation of Late Recurrence in Thai Patients With Estrogen-Receptor-Positive, Early Breast Cancer: A Validation Study.

Background: The risk of late distant recurrence (LDR) of estrogen receptor (ER)-positive breast cancer continues even after 5 years of endocrine treatment. Clinical Treatment Score after 5 years (CTS5) was developed and validated as a tool to assess the risk of LDR using data from Tamoxifen, Arimidex Alone or in Combinations (ATAC) and Breast International Group 1-98 (BIG1-98) trials. This study aimed to externally validate CTS5 in a real-world cohort of patients treated at an academic center in Thailand. Methods: The study was a retrospective analytical research study of early-stage, ER-positive breast cancer patients. The primary endpoint was LDR. The risk of LDR was determined using the CTS5 calculator. Cox regression model and Kaplan-Meier survival analysis were applied for prognostic validation of CTS5. Calibration was performed by comparing observed LDR to expected LDR using the Hosmer-Lemeshow (H-L) test. Results: A total of 323 women were included with a median follow-up period of 11.6 years. The rate of LDR was 10.8%. The CTS5 was prognostic for LDR. C-index of the area under the ROC curve was 0.672. There was no significant difference between actual and expected numbers of LDR with an observed (O) LDR events to expected (E) number of LDR events ratio of 0.99 (0.86-1.12) (H-L P = .79) indicating a proper calibration in this cohort. Conclusions: Our study validated that CTS5 is accurate in predicting the risk of LDR in ER-positive breast cancer cases in Thai patients. Its performance seemed to be better in postmenopausal patients. CTS5 could be applied in routine clinical practice to improve decisions regarding prolonged endocrine therapy, particularly in resource-limited countries where molecular profiling are inaccessible.

Healthcare coverage affects survival of EGFR-mutant Thai lung cancer patients.

Background: Despite significant benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with EGFR-mutated NSCLC, access remains limited in Thailand and elsewhere. Methods: Retrospective analysis of patients with locally advanced/recurrent NSCLC and known EGFR mutation (EGFRm) status treated at Ramathibodi Hospital (2012-2017). Prognostic factors for overall survival (OS), including treatment type and healthcare coverage, were analyzed using Cox regression. Results: Of 750 patients, 56.3% were EGFRm-positive. After first-line therapy (n=646), 29.4% received no subsequent (second-line) treatment. EGFR-TKI-treated EGFRm-positive patients survived significantly longer than EGFRm-negative patients without EGFR-TKIs (median OS [mOS] 36.4 vs. 11.9 months; hazard ratio HR=0.38 [95%CI 0.32-0.46], P<0.001). Cox regression indicated significantly longer OS in patients with comprehensive healthcare coverage that included reimbursement of EGFR-TKIs, versus basic coverage (mOS 27.2 vs. 18.3 months; adjusted HR=0.73 [95%CI 0.59-0.90]). Compared with best supportive care (BSC; reference), EGFR-TKI-treated patients survived significantly longer (mOS 36.5 months; adjusted HR (aHR)=0.26 [95%CI 0.19-0.34]), and versus chemotherapy alone (14.5 months; aHR=0.60 [95%CI 0.47-0.78]). In EGFRm-positive patients (n=422), relative survival benefit of EGFR-TKI treatment remained highly significant (aHR[EGFR-TKI]=0.19 [95%CI 0.12-0.29]; aHR(chemotherapy only)=0.50 [95%CI 0.30-0.85]; reference:BSC), indicating that healthcare coverage (reimbursement) affected treatment choice and survival. Conclusion: Our analysis describes EGFRm prevalence and survival benefit of EGFR-TKI therapy for EGFRm-positive NSCLC patients treated from 2012-2017, one of the largest such Thai datasets. Together with research by others, these findings contributed evidence supporting the decision to broaden erlotinib access on healthcare schemes in Thailand from 2021, demonstrating the value of local real-world outcome data for healthcare policy decision-making.

Disparities in Access to Systemic Treatment for Breast Cancer in Thailand and Major Asian Territories.

PURPOSE: Breast cancer (BC) treatment has shifted from chemotherapy to targeted therapy. Several targeted agents have demonstrated an improvement in survival. Given that national healthcare resources were correlated with the cancer mortality-to-incidence ratio, we compared access to BC drugs in Thailand with that in other Asian countries. METHODS: BC experts involved in the Breast International Group (BIG)-Asia in six representative groups for countries or special administrative region (SAR) in Asia (Hong Kong SAR, Japan, Korea, Taiwan, Thailand, and Singapore) were invited to participate in the survey. The questionnaire addressed national health reimbursement schemes, molecular testing for early BC (EBC), availability and accessibility of BC drugs. Accessibility and reimbursement of the drugs were reported based on their listing as essential medicines in the World Health Organization Model List of Essential Medicines (WHO-EML) and their nomination as effective drugs in the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The study was approved by all participating BIG-Asia organizations in November 2021. RESULTS: Genomic tests for EBC were non-reimbursable in all surveyed territories. Reimbursement and co-payment of BC drugs vary between and within these regions (particularly Thailand). Most drugs in the WHO-EML and ESMO-MCBS (A/B for EBC and 4/5 for advanced BC) were accessible in all surveyed territories. However, the accessibility of effective but costly WHO-EML and ESMO-MCBS drugs was not uniform in Thailand. There was an evident disparity for individuals covered by the Thai Social Security/Universal Health Coverage schemes. CONCLUSION: Essential BC drugs are generally accessible in selected BIG-Asia countries or SAR. There is a disparity in accessing high-cost drugs in Thailand compared with other Asian territories.

Optimizing outcomes for patients with metastatic prostate cancer: insights from South East Asia Expert Panel.

AIMS: Clinical decision making is challenging in men with metastatic prostate cancer (mPC), as heterogeneity in treatment options and patient characteristics have resulted in multiple scenarios with little or no evidence. The South East Asia Expert Panel 2019 addressed some of these challenges. METHODS: Based on evidence in the literature and expert interviews, 19 statements were formulated for key challenges in the treatment of men with castration-sensitive and -resistant prostate cancer in clinical practice. A modified Delphi process was used to reach consensus among experts in the panel and develop clinical practice recommendations. RESULTS: The majority of the panel preferred a risk-based stratification and recommended abiraterone or enzalutamide as first-line therapy for symptomatic chemotherapy naïve patients. Abiraterone is preferred over enzalutamide as a first-line treatment in these patients. However, the panel did not support the use of abiraterone in high risk lymph-node positive only (N+M0) or in non-metastatic (N0M0) patients. In select patients, low dose abiraterone with food may be used to optimize clinical outcomes. Androgen receptor gene splice variant status may be a useful guide to therapy. In addition, generic versions of approved therapies may improve access to treatment to a broader patient population. The choice of treatment, as well as sequencing are guided by both patient and disease characteristics, preferences, drug access, cost, and compliance. CONCLUSION: Expert recommendations are key to guidance for the optimal management of mPC. Appropriate choice, timing, and sequence of treatment options can help to tailor therapy to maximize outcomes in men with mPC.

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial.

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. Design, Setting, and Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. Main Outcomes and Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. Conclusions and Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited. Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).

Role of BIM Deletion Polymorphism and BIM Expression as Predictive Biomarkers to Maximize the Benefit of EGFR-TKI Treatment in EGFR-Positive NSCLC.

OBJECTIVE: BIM is a modulator of apoptosis that is triggered by EGFR-TKIs. This study evaluated the role of BIM deletion and its expression as predictor of EGFR-TKI treatment outcome. METHODS: The medical record of 185 EGFR-positive advanced non-small cell lung cancer (NSCLC) patients with/ without EGFR-TKI treatment between 9/2012 and 12/2014 were retrospectively reviewed. BIM deletion polymorphism and expression were tested by RT-PCR and immunohistochemistry, respectively. Survival outcomes in EGFR-TKI-treated patients were analyzed according to treatment sequence and EGFR mutation. The correlation between BIM deletion polymorphism, expression, response rate (as a function of EGFR-TKI treatment) and schedule was also explored. RESULT: EGFR-TKIs were administered to 139 (75.1%) of the 185 patients: as the first-line in 52 (37.4%) patients and as later-line treatment in 87 (62.6%) patients. Median overall survival (mOS) was significantly longer in EGFR-TKIs treated patients (28.9 vs. 7.4 months, P<0.001). Among L858R-mutated patients, median progression-free survival (mPFS) was significantly longer in first-line EGFR TKI treatment than a later-line (12.6 vs. 6.3 months, P=0.03). BIM deletion polymorphism and expression was detected in 20.2% and 52.7%, respectively. Patients without BIM deletion polymorphism had a significantly longer mOS when treated with a first-line than with a later-line EGFR-TKI (28.9 vs. 20.7 months, P= 0.04). Patients without BIM expression had a significantly longer mPFS (9.6 vs. 7.3 months, P=0.01) better mOS and response rate (RR). CONCLUSION: BIM deletion polymorphism and expression may predict an EGFR-TKI response in patients with EGFR-positive during therapy.

Sister Mary Joseph nodule caused by metastatic desmoplastic small round cell tumor: A clinicopathological report.

Sister Mary Joseph nodule is an uncommon metastatic intra-abdominal malignancy involving the umbilicus. The present study describes a rare case of desmoplastic small round cell tumor (DSRCT), histological grade 3, high grade, Gilly classification 4, stage IV, in an 18-year-old Thai man presenting with the Sister Mary Joseph nodule, ascites and pleural effusion. The histopathological examination of the umbilical mass revealed the presence of malignant small round cells associated with prominent stromal desmoplasia. Immunohistochemical stains showed positive reactivity to cytokeratin, desmin, neuron-specific enolase, Wilms' tumor 1, CD56, CD99 and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)/INI1 in the small round cells. Fine needle aspirations of the ascitic fluid and pleural effusion were performed, and immunocytochemistry revealed a metastatic DSRCT. The patient received a VDC/IE regimen of chemotherapy, comprising vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide; however, the patient developed systemic metastasis and succumbed to the disease 6 months later.