Background and Objectives: Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. Material and Methods: This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Results: Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; p = 0.00004) and median OS (35.0 vs. 23.1 months; p = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; p = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; p < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; p = 0.049). The safety profiles were consistent with previous T-DM1 studies. Conclusions: The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy.

Aim: Hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer which represents the most common subgroup of metastatic breast cancer (MBC). Recently, further subclassification for HER2-negative tumors has emerged as HER2-low. There is limited knowledge regarding the effect of HER2-low expression on outcomes of patients with HR-positive and HER2-negative MBC treated with CDK 4/6 inhibitors plus hormonal therapy. Therefore, we evaluated survival parameters according to HER2-low status for this patient group in this study. Material and Methods: As the Turkish Oncology Group (TOG) Project, retrospectively collected data from 423 patients with HR-positive/HER2-negative MBC treated with ribociclib and palbociclib plus letrozole therapy was assessed. Included patients had metastatic first-line therapy and endocrine-sensitive disease. Survival outcomes were compared between HER2-negative and HER2-low patient groups. Conclusion: HER2-low status had no statistically significant impact on survival in patients treated with palbociclib or ribociclib plus letrozole.

Background/Objectives: Neoadjuvant dual HER2 blockade is standard for HER2-positive breast cancer, yet response rates vary based on tumor biology. This multicenter study aimed to identify clinicopathological predictors of pathological complete response (pCR), focusing on quantitative hormone receptor (HR) expression and HER2 staining intensity, and to evaluate their impact on survival. Methods: This multicenter retrospective study included 290 female patients diagnosed with HER2-positive early or locally advanced breast cancer treated with neoadjuvant trastuzumab and pertuzumab-based regimens (anthracycline-based [AC-THP] or non-anthracycline [TCHP]) across six centers. HR expression was stratified into low (<50%) and high (≥50%) categories. Multivariable regression analyses identified predictors of pCR, Disease-Free Survival (DFS), and Overall Survival (OS). Results: The pCR rate was 51.4%. Multivariate analysis identified HR negativity (OR = 2.80; p < 0.001) and strong HER2 overexpression (IHC Score 3) (OR = 2.20; p = 0.037) as primary predictors. Uniquely, patients with low HR expression (<50%) achieved significantly higher pCR rates (65.9%) than strongly positive cases (36.6%; p = 0.001), biologically mimicking hormone-negative disease. The non-anthracycline TCHP regimen showed a strong trend toward superior efficacy (OR = 2.22; p = 0.054). pCR was the sole independent predictor of OS (HR = 0.134; p = 0.009). Crucially, adjusting for pCR unmasked hormone-negative status as a significant risk factor for recurrence (HR = 2.49; p = 0.028), highlighting its dual nature: high chemosensitivity but inherent biological aggression. Conclusions: “Strong” HER2 positivity and “weak” HR expression (<50%) are the primary determinants of pCR. pCR remains the strongest surrogate for survival, neutralizing initial risk factors. These findings support using quantitative biomarker thresholds for personalization and reinforce the efficacy of non-anthracycline regimens.

Background: The prognostic significance of low-level human epidermal growth factor receptor 2 (HER2) expression in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer remains unclear, particularly in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study aimed to evaluate the impact of HER2-low status on treatment response and survival outcomes in this setting. Methods: This multicenter retrospective cohort study included patients with HR+/HER2− metastatic breast cancer who received first-line endocrine therapy combined with palbociclib or ribociclib between January 2018 and May 2025. HER2-low tumors were defined as immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, while HER2-zero tumors were classified as IHC 0. Treatment response, progression-free survival (PFS), and overall survival (OS) were compared between groups using Kaplan–Meier analysis and Cox regression models. Results: A total of 309 patients were analyzed, including 122 (39.5%) with HER2-low disease and 187 (60.5%) with HER2-zero disease. Baseline clinicopathological characteristics were well balanced between groups. The overall response rate was 75.4% in the HER2-low group and 72.7% in the HER2-zero group (p > 0.05). Median PFS was 23.9 months for HER2-low patients and 25.2 months for HER2-zero patients (log-rank p = 0.785). Median OS was 49.5 and 53.1 months, respectively, with no statistically significant difference (log-rank p = 0.649). HER2 status was not an independent predictor of PFS or OS in multivariable analyses. Conclusions: In patients with HR+/HER2− metastatic breast cancer treated with first-line endocrine therapy plus CDK4/6 inhibitors, HER2-low expression was not associated with differences in treatment response or survival outcomes. These findings suggest that HER2-low status does not have prognostic or predictive relevance in this endocrine-sensitive population.

Background: First-line treatments for metastatic pancreatic cancer are chemotherapy regimens consisting of 5-fluorouracil or gemcitabine; however, there are no biomarkers to help determine which patients might benefit from which treatment regimens. We aimed to show that microRNAs let-7c and 7d can be used as independent predictive biomarkers for metastatic pancreatic cancer. Methods: A total of 55 patients who had first-line chemotherapy with FOLFIRINOX or gemcitabine+capecitabine were included. Patients were divided into groups based on let-7c and let-7d levels and chemotherapy treatment as let-7c-7d high FOLFIRINOX, let7c-7d high gemcitabine+capecitabine, let-7c-7d low FOLFIRINOX, and let-7c-7d low gemcitabine+capecitabine. Blood samples were taken from patients before chemotherapy for microRNA let-7c and 7d analysis. MicroRNA isolation was performed using a miRNeasy Serum/Plasma Kit and identified using spectrophotometric measurements. After isolation, microRNA was converted to cDNA using a microRNA cDNA Synthesis Kit with poly (A) polymerase tailing. The expression of microRNA was examined using quantitative real-time polymerase chain reaction. Results: The overall survival of patients who received FOLFIRINOX treatment with a high let-7c-7d level was statistically significantly longer than those who received gemcitabine+capecitabine with a high let-7c-7d level. In addition, patients with low let-7c expression receiving FOLFIRINOX progressed significantly 2.104 times earlier than patients with high let-7c expression receiving FOLFIRINOX. Conclusion: The serum MicroRNA let-7c level was found to be an independent predictive biomarker in the FOLFIRINOX treatment group. Cite this article as: Demiray AG, Demiray A, Yaren A, et al. Evaluation of serum microRNA let-7c and let-7d as predictive biomarkers for metastatic pancreatic cancer. Turk J Gastroenterol. 2022;33(8):696-703.