Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY.

PURPOSE: The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data. METHODS: The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC. RESULTS: Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up. CONCLUSION: The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC. CLINICAL TRIAL REGISTRATION: Clinical trials registration number: NCT03286842.

Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study.

BACKGROUND: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. METHODS: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. RESULTS: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%-49%) for pembrolizumab plus epacadostat, 21% (6%-46%) for pembrolizumab monotherapy, and 34% (19%-52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3-4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. CONCLUSIONS: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. TRIAL REGISTRATION: NCT03358472. Date of trial registration: November 30, 2017.

Impact of opioid analgesics on survival in cancer patients receiving immune checkpoint inhibitors.

PURPOSE: This study aimed to assess the effects of concurrent opioid analgesic (OA) use with immune checkpoint inhibitors (ICIs) on progression-free survival (PFS) and overall survival (OS). METHODS: In this observational retrospective study, we included advanced cancer patients who received ICIs at Hacettepe University Hospital's Department of Medical Oncology between June 2018 and January 2023. RESULTS: Our study included 375 recurrent or metastatic cancer patients treated with ICIs in the first, second line, or beyond. There were no significant differences between the OA-treated and OA-untreated groups regarding median age, age group, gender, primary tumor location, ICI type, or the presence of baseline liver and lung metastases. However, the OA-treated group exhibited a significantly higher proportion of patients who had received three or more prior treatments before initiating ICIs (p = 0.015). OA-Untreatment was significantly correlated with prolonged mPFS (6.83 vs. 4.30 months, HR 0.59, 95% CI 0.44-0.79, p < 0.001) and mOS (17.05 vs. 7.68 months, HR 0.60, 95% CI 0.45-0.80, p < 0.001). CONCLUSIONS: Our study demonstrates an association between the concurrent use of OAs and reduced OS and PFS in patients treated with ICIs. While OA treatment serves as a surrogate marker for higher disease burden, it may also suggest a potential biological relationship between opioids and immunotherapy efficacy.

The efficacy of palbociclib and ribociclib in the first-line treatment of metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer in male patients: a Turkish oncology group (TOG) study.

INTRODUCTION: Male breast cancer, comprising approximately 1% of all breast cancer cases, often leads to the exclusion of male patients as a criterion in clinical trials. While the efficacy of Cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors has been established in metastatic hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2 -) breast cancer in women, limited data exist on their effectiveness in male patients. We aimed to evaluate the efficacy and safety of palbociclib or ribociclib in male patients with breast cancer. METHODS: This study is a multicenter, retrospective study. We included male patients with HR + and HER2-metastatic breast cancer who received palbociclib or ribociclib as first-line treatment. Our primary endpoints were progression-free survival (PFS), overall response rates (ORR), and drug-related adverse effects. RESULTS: A total of 46 male patients from 27 institutions were enrolled. The median age at initiation of CDK 4/6 inhibitors was 63.64 ± 13.69 years, with a median follow-up of 21.33 (95% CI 14.92-27.74) months. The ORR were 84% for palbociclib and 76.2% for ribociclib. The mPFS for the entire cohort was 28.06 months (95% CI 18.70-37.42). No significant difference in PFS was observed between palbociclib and ribociclib (mPFS: 24.46 months (95% CI 11.51-37.42) vs 28.33 months (95% CI 14.77-41.88), respectively, p = 0.211). No new adverse events were reported. DISCUSSION: This study demonstrates that palbociclib and ribociclib are effective and safe options for first-line treatment in male patients with HR + /HER2 - metastatic breast cancer. However, further prospective studies are warranted to establish their efficacy in this population.

Real-world evaluation of nivolumab in patients with non-nasopharyngeal recurrent or metastatic head and neck cancer: a retrospective multi-center study by the Turkish Oncology Group (TOG).

OBJECTIVES: Head and neck cancers (HNCs) represent a significant global health concern due to high morbidity and mortality rates. Despite therapeutic advances, the prognosis for advanced or recurrent cases remains challenging. Nivolumab obtained approval for recurrent or metastatic HNC based on the Phase III CheckMate 141 trial. This study aimed to evaluate the real-world outcomes of nivolumab in patients with non-nasopharyngeal HNC. DESIGN: In this multicenter retrospective study, we analyzed 124 patients with recurrent or metastatic non-nasopharyngeal HNC who received nivolumab in the second-line setting and beyond. Data were collected from 20 different cancer centers across Turkey. The effectiveness and safety of the treatment and survival outcomes were evaluated. RESULTS: Nivolumab exhibited favorable clinical responses, yielding an objective response rate of 29.9% and a disease control rate of 55.7%. Safety assessments revealed a generally well-tolerated profile, with no instances of treatment discontinuation or mortality due to side effects. Survival analysis disclosed a median overall survival (OS) of 11.8 (95% CI 8.4-15.2) months. Multivariate analysis revealed that ECOG-PS ≥ 1 (HR: 1.64, p = 0.045), laryngeal location (HR: 0.531, p = 0.024), and neutrophil-to-lymphocyte ratio > 3.5 (HR: 1.97, p = 0.007) were independent predictors of OS. CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with recurrent or metastatic non-nasopharyngeal HNC in real-world settings. Further studies are needed on factors affecting response to treatment and survival outcomes.

Prognostic Significance of the Royal Marsden Hospital (RMH) Score in Patients with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance across variable clinical scenarios is not thoroughly delineated. Therefore, we aimed to systematically assess the association between RMH score and survival in cancer patients. METHODS: We conducted a systematic literature search across Pubmed, Scopus, and Web of Science databases for studies published up to 15 February 2024. We performed a meta-analysis with the generic inverse variance method with a random-effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Nineteen studies encompassing 127,230 patients were included. A higher RMH score was significantly associated with worse overall survival (OS) (HR: 2.09, 95% CI: 1.87-2.33, p < 0.001) and progression-free survival (PFS) (HR: 1.80, 95% CI: 1.48-2.18, p < 0.001). This association was consistent across various subgroups, including study population (clinical trial vs. real-world cohort), geographic region, and tumor type. CONCLUSION: This meta-analysis, including over a hundred thousand patients, demonstrates a negative association between a higher RMH score and survival in cancer patients. The RMH score holds promise as a readily available prognostic tool across diverse cancer types and clinical settings. Future research should focus on validating and refining this score to aid clinical decision-making.

Reliability and validity of the 6-minute pegboard and ring test for functional exercise capacity in patients with breast cancer.

BACKGROUND: Chronic pain, sensory disturbances, and lymphedema are frequent after breast cancer, leading to arm dysfunction. There is a need for objective performance-based clinical exercise tests for the upper extremity in patients with breast cancer. OBJECTIVE: The aim of this study was to evaluate the validity and reliability of the 6-minute pegboard and ring test (6PBRT) in breast cancer survivors. METHODS: Forty-eight women with breast cancer (mean age = 55.40 ± 10.40 years) were included. All patients performed 6PBRT on the first day and one week later to investigate the test-retest reliability of the 6PBRT, and intraclass correlation coefficients (ICC) were calculated. The peak workload (Wpeak) and oxygen consumption level (VO2peak) during the arm ergometer test were used as outcomes for the criterion validity of the 6PBRT. RESULTS: The 6PBRT showed good test - retest reliability with an ICC1,2 value of 0.871 [95% confidence interval (CI) 0.769-0.928]. The first 6PBRT score was very strongly correlated with the second test score (r = 0.866, p < .001). The 6PBRT score was significantly correlated with VO2peak (r = 0.634, p < .001), and Wpeak (r = 0.546, p < .001). While the 6PBRT score had less effect on VO2peak, the determination of VO2peak in the model was very good (R2 = 0.832). CONCLUSION: The 6PBRT has good test-retest reliability and is a valid test in individuals with breast cancer. These findings suggest that 6PBRT is a practical, useful, valid and reliable assessment tool for determining functional arm exercise capacity in patients with breast cancer.

Prognostic Significance of Pan-Immune-Inflammation Value in Patients with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab Emtansine.

Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan-Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569-0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408-3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585-3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.

Sonographic Measurements of Rectus Femoris Muscle Thickness Strongly Predict Neutropenia in Cancer Patients Receiving Chemotherapy.

The objective of this study was to explore the possible association between low skeletal muscle mass (SMM)-assessed by computed tomography (CT) and ultrasound (US)-and hematologic toxicity in cancer patients. A prospective cohort study was conducted in cancer patients who received anthracycline-based chemotherapy between 2018 and 2020 and who had baseline abdominal CT including L3 level for measuring SMM. Regional muscle measurements were carried out using US. A total of 65 patients (14 males, 51 females) were included. ROC (receiver operating characteristic) analysis identified threshold values of 18.0 mm [AUC (area under the curve) = 0.765] for females and 20.0 mm (AUC = 0.813) for males, predicting severe neutropenia. Using these cut-offs, females with low rectus femoris (RF) thickness (<18.0 mm) had a significantly higher incidence of grade ≥3 neutropenia (50.0% vs. 10.8%, p = 0.005), and males with low RF values (<20.0 mm) had a higher incidence (80.0% vs. 22.2%, p = 0.063). A regression analysis, irrespective of age, gender, and body mass index, revealed that only low RF muscle thickness increased the risk of grade 3-4 neutropenia by 9.210 times (95% CI = 2.401-35.326, p = 0.001). Utilizing US to measure RF muscle thickness aids in identifying cancer patients at an elevated risk of developing neutropenia. Needless to say, US can serve as a convenient and easily accessible tool for assessing low SMM, providing repeat point-of-care evaluations in clinical practice.

Targeting TACC3 Induces Immunogenic Cell Death and Enhances T-DM1 Response in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance. SIGNIFICANCE: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.

The impact of human epidermal growth factor receptor-2 (low) status on the efficacy of first line cyclin-dependent kinase 4/6 inhibitors in advanced breast cancer.

The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33 ±â€…0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, P = .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.

Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer.

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.

Efficacy of first-line CDK 4-6 inhibitors in premenopausal patients with metastatic breast cancer and the effect of dose reduction due to treatment-related neutropenia on efficacy: a Turkish Oncology Group (TOG) study.

The only phase 3 study on the effectiveness of CDK 4-6 inhibitors in first-line treatment in premenopausal patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer is the MONALEESA-7 study, and data on the effectiveness of palbociclib is limited. Data are also limited regarding the effectiveness of CDK 4-6 inhibitors in patients whose dose was reduced due to neutropenia, the most common side effect of CDK 4-6 inhibitors. In our study, we aimed to evaluate the effectiveness of palbociclib and ribociclib in first-line treatment in patients with premenopausal metastatic breast cancer and the effect of dose reduction due to neutropenia on progression-free survival. Our study is a multicenter, retrospective study, and factors affecting progression-free survival (PFS) were examined in patients diagnosed with metastatic premenopausal breast cancer from 29 different centers and receiving combination therapy containing palbociclib or ribociclib in the metastatic stage. 319 patients were included in the study. The mPFS for patients treated with palbociclib was 26.83 months, and for those receiving ribociclib, the mPFS was 29.86 months (p = 0.924). mPFS was 32.00 months in patients who received a reduced dose, and mPFS was 25.96 months in patients who could take the initial dose, and there was no statistical difference (p = 0.238). Liver metastasis, using a fulvestrant together with a CDK 4-6 inhibitor, ECOG PS 1 was found to be a negative prognostic factor. No new adverse events were observed. In our study, we found PFS over 27 months in patients diagnosed with premenopausal breast cancer with CDK 4-6 inhibitors used in first-line treatment, similar to post-menopausal patients. We did not detect any difference between the effectiveness of the two CDK 4-6 inhibitors, and we showed that there was no decrease in the effectiveness of the CDK 4-6 inhibitor in patients whose dose was reduced due to neutropenia.

Mean Platelet Volume to Lymphocyte Ratio: A New Biomarker Predicting Response in Patients with Solid Tumors Treated with Nivolumab.

Introduction: Although immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, identifying factors that predict treatment response remains a challenge in clinical practice. There is a need for biomarkers to identify patients who may not benefit from these treatments. It is crucial to identify a simple and cost-effective biomarker that can be easily incorporated into clinical practice. This study aims to investigate the mean platelet volume to lymphocyte ratio (MPVLR), as measured by a hemogram test, and median overall survival (mOS) in patients with cancer treated with nivolumab. Methods: A total of 131 adult patients with metastatic cancer, including malignant melanoma (MM), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and head and neck cancer (HNC), were included in this study. Baseline demographics, ECOG (Eastern Cooperative Oncology Group) performance status, tumor type, and blood count parameters were recorded. Univariate and multivariate analyses were conducted to evaluate potential risk factors. Results: The median age of the patients was 59.87 ± 11.97 years, and the median follow-up period was 20.20 months (IQR, 12.80-27.60). RCC (43.5%) and MM (25.9%) were the most common diagnoses. Patients with ECOG scores of 0-1 had a longer mOS than those with scores of 2-3 (mOS: 20.60 months [95% CI, 14.94-25.29] vs. 5.24 months [95% CI, 0-16.42], p < 0.001). Additionally, patients with lactate dehydrogenase (LDH) levels within the normal range had a longer mOS than those with high LDH levels (mOS: 24.54 months [95% CI, 14.13-34.96] vs. 13.10 months [95% CI, 4.49-21.72], p = 0.038). Patients with low MPVLR also had a longer mOS than those with high MPVLR (mOS: 33.70 months [95% CI, 25.99-41.42] vs. 11.07 months [95% CI, 6.89-15.24], p < 0.001). In the multivariate Cox regression analysis, high MPVLR, ECOG score of 2-3, and high LDH level were associated with shorter mOS (p < 0.001, p = 0.001, and p = 0.046, respectively). Conclusion: This study demonstrates that MPVLR could serve as a novel biomarker for predicting response to nivolumab treatment. Incorporating MPVLR into clinical practice may aid in identifying patients who are less likely to benefit from the treatment.

Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer.

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.