Purpose: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC. Methods: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety. Results: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed. Conclusion: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

Objective: This real-world study aimed to investigate the efficacy and safety of palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the real world in a Chinese population. Methods: The clinical data of consecutively enrolled patients from the Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, and the University of Hong Kong - Shenzhen Hospital were collected. Progression-free survival curves were generated using log-rank tests with the Kaplan-Meier method. Univariate and multivariate logistic regression analyses were performed to identify the factors affecting progression-free survival. Results: In total, 118 patients were enrolled, including 6 patients with brain metastases. At the last follow-up date, the median progression-free survival was 16.8 months (95% confidence interval, 11.1-22.5), with the 6-month and 12-month progression-free survival rates of 77.1% and 57.6%, respectively. The disease control rate and the intracranial disease control rate were 82.2% and 50%, respectively. A longer progression-free survival was observed for patients with the following characteristics: treatment-naive; without hepatic metastasis; sensitive to previous endocrine therapy and harboring fewer metastatic sites. The multivariate logistic regression analysis demonstrated that treatment lines and exposure to palliative chemotherapy were independent influencing factors of progression-free survival. Conclusions: Palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer was effective and well-tolerated, even in patients with brain metastases. More benefits were observed in frontline therapy, chemotherapy-naive, and endocrine therapy–sensitive patients with fewer metastatic sites.

Background: Small-cell lung cancer (SCLC) represents an aggressive malignancy associated with a poor prognosis, underscoring the critical demand for enhanced monitoring methodologies. Circulating tumor DNA (ctDNA) constitutes a promising non-invasive biomarker; however, reports employing highly sensitive tumor-informed assays in SCLC remain scarce. This investigation aimed to assess the clinical utility of a personalized ctDNA monitoring strategy for predicting therapeutic outcomes and resistance in SCLC patients. Methods: This prospective observational study enrolled patients diagnosed with unresectable SCLC. Whole exome sequencing was conducted on baseline tumor specimens to design customized 16-plex multiplex polymerase chain reaction (PCR) panels. Serial blood samples were obtained at baseline, at six-week intervals during treatment, and upon disease progression. Detection of ctDNA-based minimal residual disease (MRD) was performed using a tumor-informed assay (Huajianwei^® bespoke MRD) with ultra-deep sequencing. Results: Among seven evaluable patients, the baseline ctDNA-MRD positivity rate was 100%. A significant positive correlation was observed between the baseline ctDNA levels and radiographic tumor burden (r = 0.821, 95% confidence interval [CI] 0.179–0.973, p = 0.034). Longitudinal analysis indicated that patients exhibiting an early decline in MRD levels demonstrated a non-significant trend toward superior progression-free survival (PFS) compared to those with an MRD increase. Though this between-group difference did not reach conventional statistical significance, it represented a trend-level finding (p = 0.0665, hazard ratio [HR] = 0.24, 95% CI: 0.02–3.19), with no definitive prognostic association confirmed in this pilot cohort. Notably, an elevation in MRD preceded radiographic progression by as much as 135 days in certain instances. Conclusions: This study shows that dynamic tumor-informed ctDNA-based MRD monitoring reflects tumor burden changes and may correlate with clinical outcomes in SCLC, supporting its potential to guide personalized treatment and facilitate earlier therapeutic interventions compared to conventional imaging techniques. Prospective multicenter validation is needed to confirm its clinical utility.

Background: Antibiotic exposure has been associated with reduced benefit from immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). However, evidence in patients with KRAS-mutated NSCLC remains limited. This study evaluated the associations of antibiotic and probiotic exposure with survival outcomes in patients with advanced KRAS-mutated NSCLC receiving ICIs. Methods: This multicenter retrospective study included patients with advanced KRAS-mutated NSCLC who received at least one dose of ICI-based therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were performed to evaluate factors associated with survival outcomes. Results: A total of 101 patients were included, of whom 23 were exposed to antibiotics and 18 received probiotics. All patients had documented KRAS mutations. Eight patients received KRAS-targeted inhibitors after ICI progression, and none received KRAS-targeted inhibitors before or during ICI treatment. The median PFS was 9.0 months in the antibiotic-exposed group and 14.4 months in the non-antibiotic group (p = 0.041). The median OS was 23.5 and 38.4 months, respectively (p = 0.017). After multivariable adjustment, antibiotic exposure remained associated with shorter PFS (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.08–3.84; p = 0.029) and OS (HR, 2.85; 95% CI, 1.30–6.22; p = 0.009). Probiotic exposure was not significantly associated with PFS or OS. Conclusions: Antibiotic exposure was associated with shorter PFS and OS in patients with advanced KRAS-mutated NSCLC receiving ICIs, whereas probiotic exposure was not significantly associated with survival outcomes.

Background: Small-cell lung cancer (SCLC) represents an aggressive malignancy associated with a poor prognosis, underscoring the critical demand for enhanced monitoring methodologies. Circulating tumor DNA (ctDNA) constitutes a promising non-invasive biomarker; however, reports employing highly sensitive, tumor-informed assays in SCLC remain scarce. This investigation aimed to assess the clinical utility of a personalized ctDNA monitoring strategy for predicting therapeutic outcomes and resistance in SCLC patients. Methods: This prospective, observational study enrolled patients diagnosed with unresectable SCLC. Whole exome sequencing was conducted on baseline tumor specimens to design customized 16-plex multiplex PCR panels. Serial blood samples were obtained at baseline, at six-week intervals during treatment, and upon disease progression. Detection of ctDNA-based minimal residual disease (MRD) was performed using a tumor-informed assay (Huajianwei® bespoke MRD) with ultra-deep sequencing. Results: Among seven evaluable patients, the baseline ctDNA-MRD positivity rate was 100%. A significant positive correlation was observed between baseline ctDNA levels and radiographic tumor burden (r = 0.821, P = 0.034). Longitudinal analysis indicated that patients exhibiting an early decline in MRD levels (n=5) demonstrated a trend toward superior progression-free survival (PFS) compared to those with an MRD increase (n=2) (P = 0.0665, hazard ratio (HR) = 0.24 (95% CI: 0.02 - 3.19)). Notably, elevation in MRD preceded radiographic progression by as much as 135 days in certain instances. Conclusions: Tumor-informed ctDNA-MRD monitoring effectively mirrors tumor burden and offers early prediction of treatment response and clinical outcomes in SCLC. ctDNA kinetics may serve as a crucial prognostic indicator, presenting the potential to inform personalized management approaches and facilitate earlier therapeutic interventions compared to conventional imaging techniques.