First-line Chemotherapy Research Articles

A surgical orthotopic xenograft approach with immune response for colorectal cancer research.

The high morbidity and mortality of colorectal cancer (CRC) is a major challenge in clinical practice. Although a series of alternative research models of CRC have been developed, appropriate orthotopic animal models that reproduce the specific clinical response as well as pathophysiological immune features of CRC are still lacking. In the current study, we constructed a CRC orthotopic xenograft model by implanting the tumor tubes at the colorectum of mice and monitored the model development using bioluminescence imaging. This model successfully recapitulates the clinical chemotherapy efficacy, including reduced total flux, tumor weight, and the expression of Ki67 after treatment of the first-line chemotherapy regime of CRC (FOLFOX: oxaliplatin and 5-fluorouracil/calcium folinate). The model also reproduced the immunosuppressive effect of FOLFOX, indicated by decreased infiltration of macrophages and increased Treg cells in tumor. Additionally, the orthotopic xenograft approach may be applied in immunodeficient NCG/NSG mice for constructing patient-derived xenografts, and being used in clinical precision medicine and drug evaluation. We believe the current model is a successful surgical orthotopic xenograft approach for cancer research and deserves to be popularized, which will provide a convenient and efficient platform for in-depth mechanism exploration of CRC and preclinical drug evaluation.

First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial.

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg-1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .

IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies.

Treatment Patterns and Outcomes in Patients with Advanced Biliary Tract Cancers Treated with Gemcitabine-Based Chemotherapy: A Retrospective Study.

Background: Historically, the standard of care for advanced biliary tract cancers (aBTCs) was gemcitabine plus cisplatin (GemCis). Immunotherapy plus GemCis is now recommended as a first-line treatment for aBTCs. Whether patients can tolerate eight cycles of GemCis in clinical practice, as per the Advanced Biliary Cancer (ABC)-02 study, remains to be assessed. We performed a retrospective observational cohort study to assess real-world treatment patterns and overall survival (OS) in patients with de novo or recurrent aBTCs treated with first-line gemcitabine-based chemotherapy in the United States. Methods: This retrospective observational cohort study used Optum's de-identified Market Clarity Data (Market Clarity). Adults diagnosed with de novo or recurrent aBTCs in the United States who began first-line gemcitabine-based chemotherapy from January 2016-March 2022 were identified and followed from index until death, the end of continuous enrolment, or the end of study period. Treatment patterns and OS were assessed. Results: Overall, 559 patients were included (de novo, n = 462; recurrent, n = 97). GemCis was the most common first-line therapy received (de novo: 73.8%; recurrent: 57.7%). Most patients received approximately five cycles of GemCis; median (95% CI) time to discontinuation was 4.6 (4.3-5.1) months. Most patients died over the follow-up period (de novo: 70.3%; recurrent: 62.9%). Median OS (95% CI) was 14.2 (12.1-16.1) months (de novo) and 18.5 (15.6-26.9) months (recurrent). Conclusions: GemCis was the most common first-line therapy received during the study period; most patients were unable to receive eight cycles of GemCis. Survival was limited over the follow-up period, highlighting the need for new treatments for aBTCs. Future studies are warranted to understand the real-world impact of first-line immunotherapy plus GemCis for patients with aBTCs.

Clinical profile and outcomes of ocular surface squamous neoplasia at the Philippine General Hospital: a retrospective study.

To evaluate the demographics, clinical characteristics, treatments, and outcomes of patients with ocular surface squamous neoplasia (OSSN) at the Philippine General Hospital. This was a single-center, 11-year retrospective, cross sectional case series on 18 cases of OSSN seen between January 2012 to June 2023. The patient's demographics, presenting symptoms, tumor characteristics, histopathologic diagnosis, treatment, outcomes, and duration of follow-up were reviewed. Out of 33 identified cases of OSSN, only 18 were eligible for inclusion in the study. Mean age was 60.78y (range 31 to 80), with male predominance (66.67%). The left eye was most commonly affected (61.11%) with most presenting with fleshy mass (83.33%). Most tumors were located nasally (66.67%) and were predominantly papilliform (44.44%) in morphology with associated hyperpigmentation (38.89%). Squamous cell carcinoma (SCCA) was the most common histopathologic diagnosis (72.22%). The main primary treatment was surgical excision (94.44%) with or without adjunctive therapy, with only 1 patient undergoing first-line topical chemotherapy. Only 3 recurrences (16.67%) were noted with a median follow-up of 7.5mo. A statistically significant recurrence-free odds leaning towards the utilization of cryotherapy was noted. OSSN seen at the Philippine General Hospital is presented as a limbal papilliform mass, most commonly affecting elderly males. Surgical excision with adjuvant cryotherapy and/or chemotherapy is the preferred mode of treatment.

Muscle Loss During First-Line Chemotherapy Impairs Survival in Advanced Pancreatic Cancer Despite Adapted Physical Activity.

Advanced pancreatic ductal adenocarcinoma (aPDAC) is often accompanied by significant muscle mass loss, contributing to poor prognosis. SarcAPACaP, an ancillary study of the GERCOR-APACaP phase III trial, evaluated the role of adapted physical activity (APA) in aPDAC Western patients receiving first-line chemotherapy. The study aimed to assess (1) the potential impact of computed tomography (CT)-quantified muscle mass before and during treatments on health-related quality of life (HRQoL) and overall survival (OS) and (2) the role of APA in mitigating muscle mass loss. In the APACaP trial, aPDAC patients with ECOG performance status (PS) 0-2 were randomized 1:1 to usual care including first-line chemotherapy or usual care plus a 16-week home-based APA program. In the SarcAPACaP study, the surface muscular index (SMI) was determined from L3 CT scan slices. Two patient populations were analysed: those with CT scan available at baseline (modified[m] intent-to-treat [ITT]1-W0) and those with CT scans available at both W0 and W16 (mITT2 W0-W16). Low muscle mass was defined by low SMI with SMI < 41 cm2/m2 for women and < 43 and < 53 cm2/m2 for men with body max index < 25.0 and ≥ 25.0 kg/m2, respectively. Muscle loss was defined by the relative difference of SMI between W0 and W16 (100*[SMI W16-SMI W0]/SMI W0). In mITT2 W0-W16, patients were stratified into three groups based on the severity of muscle loss: none, moderate (0%-10%) and high (≥ 10%). Associations between muscle mass loss and OS, time until definitive deterioration (TUDD) of HRQoL and the effect of APA on loss of muscle mass were assessed. Between October 2014 and May 2020, 313 patients were prospectively enrolled, with 225 in mITT1 W0 and 128 in mITT2 W0-W16, with 65 assigned to the APA arm. Both groups had similar baseline characteristics with comparable OS and TUDD. A low SMI at W0 was not associated with OS and TUDD of HRQoL in either group. Among mITT2 W0-W16 patients, high muscle mass loss (n = 27) independently predicted OS (p = 0.012) and showed a trend toward negatively affecting TUDD of HRQoL. Notably, APA did not mitigate muscle loss in our study population. Longitudinal muscle mass loss emerged as a predictive factor for both OS and HRQoL in aPDAC patients undergoing chemotherapy, while a low SMI at diagnosis did not provide prognostic value. APA did not impact muscle mass loss in this population.

Clinical outcomes and treatment patterns of maintenance avelumab in locally advanced or metastatic urothelial carcinoma: a multicenter collaborative study.

The JAVELIN Bladder 100 trial demonstrated improved overall survival (OS) with maintenance avelumab in patients with locally advanced or metastatic urothelial carcinoma UC (la/mUC) who achieved disease control following first-line platinum-based chemotherapy (1L-PBC). However, real-world data on eligibility, utilization, and outcomes of maintenance avelumab therapy remain limited. This retrospective study included patients with la/mUC who received 1L-PBC. Eligibility for maintenance avelumab therapy was determined based on the best overall response to 1L-PBC, with patients who achieved stable disease or a partial or complete response considered eligible. Survival outcomes were analyzed using the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify prognostic factors among patients with la/mUC who received maintenance avelumab. Of 161 prospective patients, 67.1% were eligible for maintenance avelumab therapy, and 46.3% of eligible patients received the treatment. The median progression-free survival (PFS) following avelumab initiation was 10.2months, whereas the median OS was not reached. Prognostic factors associated with PFS included the presence of liver metastases, elevated C-reactive protein (> 1.0g/dL), and administration of more than five cycles of 1L-PBC. Adverse events occurred in 60% of patients treated with avelumab, with 16% experiencing grade 3-4 adverse events. We emphasize the real-world applicability of maintenance avelumab for Japanese patients with la/mUC. Maintenance avelumab demonstrated favorable survival outcomes, consistent with clinical trial data. Identifying prognostic factors and optimizing treatment sequencing are essential strategies for improving outcomes in this patient population.

Real-world outcomes of first-line maintenance niraparib monotherapy in patients with epithelial ovarian cancer.

To assess real-world progression-free survival (rwPFS) and time to next treatment (rwTTNT) among patients with epithelial ovarian cancer (EOC) who received first-line maintenance (1LM) niraparib monotherapy. In this US-nationwide, electronic health record-derived, deidentified database study, eligible patients with EOC initiated 1LM niraparib monotherapy (1 January 2017-1 December 2022) following first-line platinum-based chemotherapy. Median rwPFS and rwTTNT were estimated with Kaplan-Meier methodology overall and in a homologous recombination-deficient (HRd) subgroup (further stratified as BRCA wild-type [BRCAwt] or BRCA-mutated [BRCAm]). Observed median rwPFS was 11.4 (95% CI, 10.1-12.7) months overall (N = 560), 18.2 (95% CI, 13.9-24.2) months for the HRd subgroup (n = 144), and 25.4 (95% CI, 15.9-not reached) and 14.2 (95% CI, 8.6-18.6) months for HRd patients with BRCAm and BRCAwt tumors, respectively. Observed median rwTTNT was 12.4 (95% CI, 11.5-13.8) months overall, 19.6 (95% CI, 14.9-23.9) months for the HRd subgroup, and 24.9 (95% CI, 16.0-not reached) and 15.1 (95% CI, 10.3-19.8) months for HRd patients with BRCAm and BRCAwt tumors, respectively. The real-world observed median rwPFS and rwTTNT were longer for patients with EOC who received 1LM niraparib monotherapy in the HRd subgroup (specifically for the BRCAm subgroup).

Durable and Drastic Response to the Trastuzumab, Letrozole, Abemaciclib, and Goserelin Combination as First-Line Therapy in HER2-Positive and Hormone Receptor-Positive Metastatic Breast Cancer: A Case Report

Introduction: Chemotherapy combined with anti-human epidermal growth factor receptor 2 (HER2)-targeted therapy is currently a standard treatment for advanced HER2/HR-positive breast cancer (BC), although evidences showed that HR expression compromised effectiveness of the treatment. While cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy is a key therapy for the BC with HR expression, data on the effectiveness and safety of CDK 4/6 inhibitors combined with trastuzumab and endocrine therapy as a first-line treatment for HER2-positive and HR-positive metastatic BC are limited. Case Presentation: Here, we report a case of a 46-year-old premenopausal woman diagnosed with stage 4 HER2/HR-positive invasive ductal carcinoma from both right and left breast with hypermetabolic activities in multiple lymph nodes, adrenal, bone, and skin. Interventions: Due to the patient’s refusal to use chemotherapy, she was started on goserelin, abemaciclib, letrozole, and trastuzumab. Outcomes: The patient’s symptoms were relieved with near resolution of the primary breast mass and nearly all of the metastatic sites. Metabolic resolution was observed in bone lesions. The disease was under control for 57 weeks. During the treatment, neutropenia (grade 1–2) and anemia (grade 1) occurred, which spontaneously recovered. Additionally, diarrhea improved after symptomatic treatment. Conclusion: We believe that the combination of trastuzumab, hormone suppression, and abemaciclib is a practicable and effective treatment for HER2-positive and HR-positive metastatic BC in premenopausal patients who cannot tolerate the first-line chemotherapy.

Comprehensive Characterization via Molecular Imaging, Longitudinal Multisite Sampling, and Autoptic Work-up in Advanced Small Cell Lung Cancer Undergoing SSTR-Directed Radiopharmaceutical Therapy.

Despite the addition of immune checkpoint blockade to first-line chemotherapy, the prognosis for patients with small cell lung cancer (SCLC) is still devastating. For the subset of SCLC with somatostatin receptor (SSTR) overexpression, radiopharmaceutical therapy (RPT) might be an effective future treatment option. Methods: Here, we present the case of a heavily pretreated stage IV SCLC patient showing an exceptional response to SSTR-directed RPT. A comprehensive translational work-up consisting of histopathologic, immunohistochemical, and molecular pathology analyses at different time points during treatment and especially of lesions with discordant tracer uptake was performed. Results: Besides a promising response to RPT, interesting signs of clonal dynamics under therapy and, most importantly, SSTR downregulation of some lesions as a potential evasion mechanism to SSTR-directed RPT could be identified. Conclusion: This unique investigation for a clinical-molecular understanding of novel treatment paradigms in SCLC may provide the basis for future treatment designs.

Primary Effusion Lymphoma Prognostic Score (PEL-PS): A Validated International Prognostic Score in HIV-Associated Primary Effusion Lymphoma.

Primary effusion lymphoma (PEL) is an HIV-associated B-cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV). There is no validated prognostic model in PEL, and prognosis is thought to be poor compared to other HIV-associated NHL. We derived the PEL-Prognostic score (PEL-PS) from an international real-world training set of 59 patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy from the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and the National Center for HIV Malignancy at the Chelsea and Westminster Hospital (CWH) in England from 2000 to 2022. We identified prognostic factors associated with overall survival (OS). In a multivariable Cox model, ECOG ≥ 3 (p = 0.007; hazard ratio [HR] = 4.0 [95% CI: 1.5-11.1]) and hemoglobin < 8 g/dL (p = 0.006; HR = 3.8 [95% CI: 1.5-9.7]) were jointly associated with lower survival probability. The resulting PEL-PS separated patients with no negative prognostic factors (score 0: hemoglobin ≥ 8 g/dL and ECOG ≤ 2, 48.1% of patients) with median OS of 10.6 years versus patients with 1-2 negative prognostic factors (score 1-2: hemoglobin < 8 g/dL and/or ECOG ≥ 3, 51.9% of patients) with median OS of 0.8 years (p < 0.0001). The PEL-PS was then validated in 58 patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at Hôpital Saint-Louis in France over the same period: median OS in patients with PEL-PS 0 was 16.9 years versus 0.6 years in patients with PEL-PS score of 1-2 (p < 0.0001). The PEL-PS identifies patients with good and poor prognosis. Patients with poor prognosis may benefit from novel therapies.

Pre-treatment nutrition-related indicators and the prognosis of patients with newly diagnosed epithelial ovarian cancer: an ambispective cohort study

BackgroundFew studies have explored the link between nutritional status and prognosis in patients with epithelial ovarian cancer (EOC), and existing findings are controversial. Thus, this study aimed to explore the effects of pre-treatment nutrition-related indicators on the prognosis of patients with newly diagnosed EOC.MethodsIn this ambispective cohort study, 1,020 patients with EOC diagnosed by pathology examination were enrolled and followed-up until December 31, 2023. Univariate and multivariable analyses were conducted on nutrition-related indicators, including body mass index (BMI), albumin (ALB), hemoglobin (Hb), diabetes mellitus (DM), and hyperlipidemia, along with clinicopathological characteristics that might affect patients’ first-line chemotherapy response, progression-free survival (PFS), and overall survival (OS). Survival curves were created using the Kaplan–Meier method. A Cox proportional hazards model was established to obtain hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsThe median follow-up duration was 48 months. Compared with patients having normal nutritional indicators, those with hypoalbuminemia had poorer first-line chemotherapy responses. The proportions of those with complete response (CR), partial response (PR), and stable disease or progressive disease (SD/PD) for the ≤30 g/L, 30 &amp;lt; ALB&amp;lt;35 g/L and normal ALB groups were 57.2, 20.6, and 22.2% vs. 62.0, 22.5, and 15.5% vs.79.5, 13.6, and 6.9%. Patients with hypoalbuminemia had shorter median PFS (mPFS): 15 vs. 19 vs. 57 months in the three groups, respectively; and shorter median OS (mOS): 36 vs. 51 vs. 124 months. Patients with hyperlipidemia also exhibited poorer first-line chemotherapy responses; CR, PR, and SD/PD rates for the hyperlipidemia and non-hyperlipidemia groups were 68.9, 19.5, and 11.6% vs. 76.4, 14.7, and 8.9%, respectively, and shorter mPFS (17 vs. 57 months) and mOS (40 vs. 119 months). Patients with anemia had poorer first-line chemotherapy responses; CR, PR, and SD/PD rates for the anemia and non-anemia groups were 68.4, 19.7, and 11.9% vs. 76.2, 14.9, and 8.9%, respectively. All differences were statistically significant (p &amp;lt; 0.05). Multivariable analysis identified hyperlipidemia as an independent risk factor for PFS (hazard ratio [HR] = 2.083; 95% CI:1.726–2.514; p &amp;lt; 0.001) and OS (HR = 2.158; 95% CI:1.746–2.666; p &amp;lt; 0.001), whereas hypoalbuminemia and anemia were not confirmed as independent prognostic factors. This study found no effect of BMI or DM on patient prognosis.ConclusionPre-treatment hypoalbuminemia, hyperlipidemia, and anemia negatively affected the prognosis of patients with newly diagnosed EOC, with hyperlipidemia being an independent risk factor for shorter survival.

Second-Line Treatment Options for Patients with Metastatic Triple-Negative Breast Cancer: A Review of the Clinical Evidence.

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial.

Cemiplimab has demonstrated significantly longer survival than physician's choice of chemotherapy in patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. We report the final survival analysis from the phase III randomized study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9). Cemiplimab (n=304) or chemotherapy (n=304) were administered every 3 weeks. The primary endpoint was overall survival (OS). Patients were included regardless of programmed cell death-ligand 1 (PD-L1) status. At a median follow-up of 47.3 months (data cut-off: April 20, 2023), median OS was 11.7 versus 8.5 months for patients treated with cemiplimab and chemotherapy, respectively (hazard ratio 0.67, 95% confidence interval 0.56-0.80, p<.00001). OS benefit was seen in PD-L1 positive and negative populations, even though more patients with PD-L1<1% (n=92), had poor performance status in the cemiplimab arm than the chemotherapy arm (61.4% vs 47.9%). This final analysis confirms that cemiplimab maintains survival benefit compared with chemotherapy in recurrent cervical cancer after progression on first-line platinum therapy, regardless of PD-L1 expression. The safety profile was consistent with published data; incidences of adverse events were similar between cemiplimab and chemotherapy groups. These results support the use of second-line cemiplimab for patients with recurrent cervical cancer.

Trastuzumab-Pertuzumab Plus Eribulin or Taxane as First-Line Chemotherapy for Human Epidermal Growth Factor 2-Positive Locally Advanced/Metastatic Breast Cancer: The Randomized Noninferiority Phase III EMERALD Trial.

Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC. In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.gov identifier: NCT03264547/UMIN000027938), patients were randomly assigned (1:1) to receive eribulin 1.4 mg/m2 once daily on days 1 and 8 (eribulin group) or a taxane (docetaxel 75 mg/m2 once on day 1 or paclitaxel 80 mg/m2 once daily on days 1, 8, and 15; taxane group) intravenously in a 21-day cycle, each with HP on day 1. The primary end point was progression-free survival (PFS; intention-to-treat population). Secondary end points included objective response rate, overall survival (OS), patient-reported quality of life (QoL), and safety. Noninferiority was tested using the stratified Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events, with a noninferiority HR margin of 1.33. Between August 2017 and June 2021, 446 patients (median age, 56.0 years) were enrolled. The median PFS was 14.0 and 12.9 months in the eribulin group (n = 224) and taxane group (n = 222 [docetaxel/paclitaxel, n = 186/36]), respectively (HR, 0.95 [95% CI, 0.76 to 1.19]), which confirmed the noninferiority of the study regimen. The median OS was 65.3 months in the taxane group but has not been reached in the eribulin group. Median time to QoL deterioration was numerically longer with eribulin than with taxane. Adverse event (AE) rates were similar, despite the longer duration of eribulin use. Infusion reaction, skin-related AEs, diarrhea, and edema were more common with taxane, whereas neutropenia was more common with eribulin. The results suggested that eribulin + HP is an option for first-line treatment of locally advanced/metastatic HER2+ BC.

Knockdown of LAMA3 enhances the sensitivity of colon cancer to oxaliplatin by regulating the Hippo-YAP pathway.

Oxaliplatin is the first-line chemotherapy for patients with colon cancer (CC). However, its resistance limits its therapeutic efficacy. Oxaliplatin resistance-associated differentially expressed genes (DEGs) in the GSE42387 and GSE227315 datasets were identified through bioinformatics methods. Functional experiments were conducted both in vitro and in vivo to evaluate the roles of laminin subunit alpha 3 (LAMA3) in drug resistance and tumorigenesis. The downstream molecular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and western blot. Six hub genes associated with oxaliplatin resistance were identified, including LAMB3, ITGA3, COL4A6, COL12A1, LAMA3, and LAMC2, all of which were highly expressed in oxaliplatin-resistant CC cell lines. LAMA3 knockdown sensitized CC cells to oxaliplatin treatment, resulting in further inhibition of proliferation, migration, and invasion, as well as an increase in apoptosis in CC cells. Additionally, LAMA3 knockdown promoted the therapeutic efficacy of oxaliplatin in the CC xenograft tumor models. Mechanistically, overexpression of YAP notably counteracted the enhanced sensitivity to oxaliplatin caused by LAMA3 knockdown, indicating that LAMA3 modulates oxaliplatin sensitivity in CC through the Hippo-YAP pathway. LAMA3 knockdown promotes CC sensitivity to oxaliplatin via modulating the Hippo-YAP pathway, providing new therapeutic targets for the CC treatment.

Exploring Prognostic Factors and Survival Outcomes in Advanced Non-Small Cell Lung Cancer Patients Undergoing First-Line Chemotherapy in Limited-Resource Settings.

Background/Objectives: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, especially in limited-resource countries (LRCs) where access to advanced treatments such as targeted therapy and immunotherapy is constrained. Platinum-based chemotherapy remains a cornerstone of first-line therapy. This study aims to identify prognostic factors influencing survival outcomes and evaluate treatment response to chemotherapy in advanced NSCLC patients in LRCs. Methods: A retrospective cohort study was conducted on 200 advanced NSCLC patients treated with first-line platinum-based doublet chemotherapy at Surin Hospital Cancer Center, Thailand. Prognostic factors were assessed through univariate and multivariate Cox regression analyses. Additionally, restricted mean survival time (RMST) was calculated to compare survival outcomes between responders and non-responders. Results: Independent prognostic factors associated with improved survival included good performance status, ECOG 0-1 (HR 0.50, p = 0.012), serum albumin ≥ 3.5 mg/dL (HR 0.60, p = 0.010), and favorable response to chemotherapy (HR 0.57, p = 0.003). Responders demonstrated significantly longer RMST at 12 months (p < 0.001), 24 months (p < 0.001), and 36 months (p = 0.004) compared to non-responders. Conclusions: Identifying prognostic factors and treatment responses is important for improving outcomes in advanced NSCLC patients, particularly in limited-resource settings where access to novel therapies is restricted.

Assessment of heterogeneity according to hospital or medical experience factors in outcomes of chemotherapy for advanced biliary tract cancer: a post-hoc analysis of JCOG1113.

JCOG1113 is a randomized phase III trial that showed non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin in patients with advanced biliary tract cancer. Assessment of inter-institutional heterogeneity in chemotherapy contributes to confirm generalizability and reliability of the study itself. However, there have been no studies conducted to assess the heterogeneity among participating centers in randomized phase III trials for biliary tract cancer. The objective of this post-hoc analysis was to assess the inter-institutional heterogeneity in the overall survival and progression-free survival of patients with advanced biliary tract cancer treated with first-line chemotherapy in the JCOG1113 trial. The heterogeneity in the overall survival and progression-free survival was assessed according to three factors: hospital volume, experience in medical oncology and experience in biliary intervention. A total of 300 advanced biliary tract cancer patients were analyzed. There were no statistically significant trends observed between hospital volume, experience in medical oncology, or experience in biliary intervention and overall survival (hospital volume: adjusted trend P value=0.6796; experience in medical oncology: adjusted trend P value=0.4092; experience in biliary intervention: adjusted trend P value=0.6112). Similarly, no statistically significant trends were observed between these factors and progression-free survival (hospital volume: adjusted trend P value=0.3000; experience in medical oncology: adjusted trend P value=0.1108; experience in biliary intervention: adjusted trend P value=0.2898). This study revealed no inter-institutional heterogeneity in the overall survival and progression-free survival in the JCOG1113 study population of advanced biliary tract cancer patients.

A Comparative Study On The Progression Of Neuroendocrine Carcinomas and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

The prognostic differences between neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) remain unclear. This study aims to compare the prognostic outcomes of NEC and MiNEN by analyzing the clinicopathological features of these diseases and exploring factors affecting progression after radical surgery. Additionally, we employed whole-exome sequencing to investigate the molecular mechanisms influencing the prognosis of both conditions. Among the 252 patients followed, 163 underwent surgical treatment. The median time to tumor progression was 16 months (range: 9 to 56 months). Tumor pathology type (P=0.007), lymph node metastasis (P<0.0001), and distant metastasis (P<0.0001) were identified as independent factors affecting disease progression in NEC and MiNEN patients. MiNEN patients without lymph node or distant metastasis generally had a better prognosis. First-line chemotherapy regimens did not show a significant impact on disease progression (P=0.160, mPFS: 36 vs 13 vs 23 vs 15 months). However, the EP (etoposide plus cisplatin) regimen has shown good efficacy in gastric NENs (neuroendocrine neoplasms) (P=0.048, mPFS: 45 vs 12 vs 32 vs 16 months), especially in gastric MiNENs (P=0.022, mPFS: Undefined vs 11 vs 52 vs 37 months). Further investigation into the genetic mutation differences between NECs and MiNENs revealed that among previously sequenced data, rectal NECs commonly exhibited mutations in MUC16, SPTA1, ATM, PDGFB, NF1, FAT4, AR, APC, ANTXR2, and ADGRA2. In contrast, rectal MiNENs showed common mutations in NOTCH2, ZNRF3, CARD11, TP53, OBSCN, FPR1, APC, ANGPT2, ARID1A, and AR. Mutations in ANGPT2 and OBSCN were present in two rectal MiNEN cases, while NF1 and PDGFB mutations were found in two rectal NEC cases but not in MiNENs. The JAK-STAT signaling pathway appears to be specific to rectal NECs and may be involved in tumor progression. EP regimen remains the most effective chemotherapy option for neuroendocrine tumor patients. There were prognostic differences between NECs and MiNENs, as well as differences in genetic mutations and signaling pathways. This study provided new insights into the prognosis assessment and treatment strategies for NENs, particularly highlighting the importance of personalized treatments and the development of novel targeted therapies.

Efficacy of Adding Locoregional Therapy in ATZ/BEV-Treated Patients with Stable HCC.

Background/Objectives: Combination therapy with atezolizumab and bevacizumab (ATZ/BEV) is extremely effective and yields a high response rate in patients with hepatocellular carcinoma (HCC). In this study, the efficacy of adding locoregional therapy to ATZ/BEV in patients with stable disease (SD) HCC was investigated. Methods: One hundred five HCC patients who were treated with ATZ/BEV or lenvatinib (LEN) as first-line chemotherapy for unresectable HCC were evaluated on the basis of the modified RECIST criteria. SD patients whose initial antitumor effect was achieved received locoregional therapy, and the overall survival (OS) rate was assessed. Results: This study included 58 ATZ/BEV-treated participants and 47 LEN-treated participants. Twenty-eight SD patients (ATZ/BEV) and 20 SD patients (LEN) were identified. OS was significantly greater in ATZ/BEV-treated patients who also received locoregional therapy than in those who did not receive this additional therapy (p = 0.0343), whereas there was no difference between LEN-treated patients who also received locoregional therapy and those who did not. The locoregional therapy consisted of transcatheter arterial chemoembolization (TACE) and/or radiofrequency ablation (RFA). When assessing the add-on effect of TACE and/or RFA in the SD patients treated with ATZ/BEV, five patients were found to achieve CR. Conclusions: The addition of locoregional therapy, such as TACE/RFA, was found to affect SD patients. When a response is limited during ATZ/BEV therapy, it is important to consider the therapeutic option of adding locoregional therapy, as this additional treatment may contribute to improved prognosis via immune modulation.