Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (E20ins) are the third most frequent mutations observed in non-small cell lung cancer, accounting for approximately 1-10% of all EGFR mutations. In the era of precision medicine and targeted therapies, consistent naming of genetic alterations is crucial to avoid confusion and errors. However, the annotation of EGFR E20ins mutations has been inconsistent, leading to confusion in the scientific literature and product documentation. In this study, our primary objective was to investigate the usage of different annotation related to EGFR E20ins in independent studies. Additionally, we assessed the distribution of EGFR E20ins mutations and estimated the detection coverage expected from each available EGFR E20ins detection assay. A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. Our analysis revealed that the majority of EGFR E20ins mutations requiring correction were 'insertion' or 'deletion-insertion', which should be appropriately designated as 'duplication'. Additionally, duplicated variants were reported using different annotations in each study, and furthermore, even identical variant sequences were annotated differently within the same study. In all six studies, p.A767_V769dup and p.S768_D770dup were the most frequently observed EGFR E20ins. The Oncomine Dx Target Test showed the highest patient coverage at 77.2%, followed by the Droplex EGFR Mutation Test v2 with a patient coverage of 70.5% for EGFR E20ins patients. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur.

Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application.

Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.

PTK2 is a potential biomarker and therapeutic target for EGFR- or TLRs-induced lung cancer progression via the regulation of the cross-talk between EGFR- and TLRs-mediated signals.

Protein tyrosine kinase 2 (PTK2), epidermal growth factor receptor (EGFR), and toll-like receptor (TLRs) are amplified in non-small cell lung cancer (NSCLC). However, the functional and clinical associations between them have not been elucidated yet in NSCLC. By using microarray data of non-small cell lung cancer (NSCLC) tumor tissues and matched normal tissues of 42 NSCLC patients, the genetic and clinical associations between PTK2, EGFR, and TLRs were analyzed in NSCLC patients. To verify the functional association, we generated PTK2-knockout (PTK2-KO) lung cancer cells by using CRISPR-Cas9 gene editing method, and performed in vitro cancer progression assay, including 3D tumor spheroid assay, and in vivo xenografted NSG (NOD/SCID/IL-2Rγnull) mouse assay. Finally, therapeutic effects targeted to PTK2 in lung cancer in response to EGF and TLR agonists were verified by using its inhibitor (Defactinib). In summary, we identified that up-regulated PTK2 might be a reliable marker for EGFR- or TLRs-induced lung cancer progression in NSCLC patients via the regulation of the cross-talk between EGFR- and TLRs-mediated signaling. This study provides a theoretical basis for the therapeutic intervention of PTK2 targeting EGFR- or TLRs-induced lung cancer progression.

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States.

Aim: To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Methods: A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes. Results: When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments. Conclusion: Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors.

Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare, recurrent oncogenic variant that constitutively activates EGFR in non-small-cell lung cancer. Herein, we report the case of a 70-year-old man with resectable colorectal adenocarcinoma who underwent surgery followed by adjuvant therapy. He relapsed with multiple liver metastases and received standard chemotherapy until his disease became refractory. Comprehensive genomic profiling of his postoperative colorectal cancer tissue revealed EGFR-KDD. He was treated with an EGFR tyrosine kinase inhibitor (TKI), afatinib and achieved a partial response (- 55%) after 8 weeks; however, he developed massive malignant ascites after 13 weeks. Osimertinib, another EGFR-TKI, controlled his tumors for 9 months. Patient-derived cancer organoids from his malignant ascites confirmed sensitivity to EGFR-TKIs. The findings suggest that EGFR-TKIs can be a potential treatment option for this molecular subgroup.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

The predictive value of serum tumor markers for EGFR mutation in non-small cell lung cancer patients with non-stage IA.

Objective: The predictive value of serum tumor markers (STMs) in assessing epidermal growth factor receptor (EGFR) mutations among patients with non-small cell lung cancer (NSCLC), particularly those with non-stage IA, remains poorly understood. The objective of this study is to construct a predictive model comprising STMs and additional clinical characteristics, aiming to achieve precise prediction of EGFR mutations through noninvasive means. Materials and methods: We retrospectively collected 6711 NSCLC patients who underwent EGFR gene testing. Ultimately, 3221 stage IA patients and 1442 non-stage IA patients were analyzed to evaluate the potential predictive value of several clinical characteristics and STMs for EGFR mutations. Results: EGFR mutations were detected in 3866 patients (57.9 %) of all NSCLC patients. None of the STMs emerged as significant predictor for predicting EGFR mutations in stage IA patients. Patients with non-stage IA were divided into the study group (n = 1043) and validation group (n = 399). In the study group, univariate analysis revealed significant associations between EGFR mutations and the STMs (carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin-19 fragment (CYFRA21-1)). The nomogram incorporating CEA, CYFRA 21-1, pathology, gender, and smoking history for predicting EGFR mutations with non-stage IA was constructed using the results of multivariate analysis. The area under the curve (AUC = 0.780) and decision curve analysis demonstrated favorable predictive performance and clinical utility of nomogram. Additionally, the Random Forest model also demonstrated the highest average C-index of 0.793 among the eight machine learning algorithms, showcasing superior predictive efficiency. Conclusion: CYFRA21-1 and CEA have been identified as crucial factors for predicting EGFR mutations in non-stage IA NSCLC patients. The nomogram and 8 machine learning models that combined STMs with other clinical factors could effectively predict the probability of EGFR mutations.

Do proton pump inhibitors affect the effectiveness of cyclin-dependent kinase 4/6 inhibitors in advanced HR positive, HER2 negative breast cancer? A meta-analysis.

Background: The CDK 4/6 inhibitors, including palbociclib and ribociclib, are the standard first-line treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Proton pump inhibitors are one of the most globally prescribed types of medications as part of the treatment for gastroesophageal reflux and heartburn complaints. Medication interactions have been demonstrated, leading to a decrease in the effectiveness of chemotherapy drugs such as capecitabine and pazopanib. However, their role and interaction with targeted therapies such as CDK inhibitors are still poorly understood. Methods: We searched PubMed, Embase and Web of Science databases for studies that investigated the use of PPI with CDK 4/6 inhibitors versus CDK4/6 alone for advanced or metastatic breast cancer. We systematically searched for the currently available CDK inhibitors: palbociclib, ribociclib and abemaciclib. We computed hazard ratios (HRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses. Results: A total of 2,737 patients with advanced breast cancer in 9 studies were included, with six studies described the status menopausal as 217 (7.9%) pre-menopause and 1851 (67.6%) post-menopause, for endocrine sensitivity only five studies described1489 (54.4%) patients were endocrine-sensitive and 498 (182%) endocrine-resistent, 910 (33.2%) patients used PPIs. The overall Progression-Free Survival was in favor of the PPI non-users (HR 2.0901; 95% CI 1.410-2.9498; p < 0.001). As well as the subgroup taking palbociclib, revealing statistical relevance for the PPI non-users (HR 2.2539; 95% CI 1.3213-3.8446; p = 0.003) and ribociclib subgroup with a slight decrease in hazard ratio (HR 1.74 95% CI 1.02-2.97; p = 0.04; I2 = 40%). In the multivariate analysis, there was no statistical signifance with ECOG (HR 0.9081; 95% CI 0.4978-16566; p 0.753) and Age (HR 1.2772; 95% CI 0.8790-1.8559; p = 0.199). Either, the univariate analysis did not show statistical significance. Conclusion: Women with HR+ and HER2-advanced metastatic breast undergoing treatment with targeted therapies, specifically CDK 4/6 inhibitors, should be monitored for the use of proton pump inhibitors. Therefore, the use of PPIs should be discussed, weighing the advantages and disadvantages for specific cases. It should be individualized based on the necessity in clinical practice for these cases. Systematic Review Registration: identifier CRD42023484755.

Efficacy of targeted therapy in patients with non-small cell lung cancer harboring very rare mutations in EGFR exon 18.

Background: Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Methods: This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Results: Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). Conclusions: EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

Subregion-specific 18F-FDG PET-CT radiomics for the pre-treatment prediction of EGFR mutation status in solid lung adenocarcinoma.

This study aimed to assess the efficacy of fluor-18 fluorodeoxyglucose (18F-FDG) PET/CT using sub-regional-based radiomics in predicting epidermal growth factor receptor (EGFR) mutation status in pretreatment patients with solid lung adenocarcinoma. A retrospective analysis included 269 patients (134 EGFR+ and 135 EGFR-) who underwent pretreatment 18F-FDG PET/CT scans and EGFR mutation testing. The most metabolically active intratumoral sub-region was identified, and radiomics features from whole tumors or sub-regional regions were used to build classification models. The dataset was split into a 7:3 ratio for training and independent testing. Feature subsets were determined by Pearson correlation and the Kruskal Wallis test and radiomics classifiers were built with support vector machines or logistic regressions. Evaluation metrics, including accuracy, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were employed for different classifiers. Results indicated that the sub-region-based classifier outperformed the whole-tumor classifier in terms of accuracy (73.8% vs. 66.2%), AUC (0.768 vs. 0.632), specificity (65.0% vs. 50.0%), PPV (70.2% vs. 62.2%), and NPV (78.8% vs. 74.0%). The clinical classifier exhibited an accuracy of 75.0%, AUC of 0.768, sensitivity of 72.5%, specificity of 77.5%, PPV of 76.3%, and NPV of 73.8%. The combined classifier, incorporating sub-region analysis and clinical parameters, demonstrated further improvement with an accuracy of 77.5%, AUC of 0.807, sensitivity of 77.5%, specificity of 77.5%, and NPV of 77.5%. The study suggests that sub-region-based 18F-FDG PET/CT radiomics enhances EGFR mutation prediction in solid lung adenocarcinoma, providing a practical and cost-efficient alternative to invasive EGFR testing.

Association between human epidermal growth factor receptor 2 status, namely low and zero expression, and prognosis in hormone receptor-positive breast cancer: a single-center retrospective study.

Background: The recently developed anti-human epidermal growth factor receptor 2 (HER2) therapy has substantially improved the prognosis of HER2-positive breast cancer. The DESTINY-Breast04 trial results showed that trastuzumab deruxtecan (T-DXd) significantly prolonged the survival of patients with HER2-low breast cancer, thus presenting a paradigm shift in anti-HER2 therapy. This may facilitate a change in the treatment strategy for HER2-low breast cancer. However, the implication of HER2-low in hormone receptor (HR)-positive breast cancer is unclear. In this retrospective study, we aimed to reveal the association between HER2 status, namely HER2-low and HER2-zero, and prognosis in HR-positive breast cancer. Methods: We collected the data of 247 patients with estrogen receptor (ER)-positive/HER2-negative breast cancer (159 with HER2-low and 88 with HER2-zero breast cancer) who underwent surgery. Patients were divided into HER2-low and HER2-zero groups. Univariate analysis was performed to evaluate the baseline characteristics using the Wilcoxon rank sum test and Fisher's exact test. Survival analysis of the HER2-low and HER2-zero groups was performed using the Kaplan-Meier method. Results: The median observation period was 2,706 days, and the median period until recurrence was 1,380 days; 25 patients (10%) had recurrences. Age (P=0.004) and menopausal status (P=0.04) were significant variables in the univariate analysis of baseline characteristics. In the subgroup analysis of luminal A- and B-like breast cancers, there was a significant difference in overall survival (OS) only in patients with luminal A-like breast cancer, but relapse-free survival (RFS) of the HER2-low luminal B-like cancer subgroups tended to be relatively short. Conclusions: We inferred that the HER2-low and HER2-zero statuses do not affect the RFS and OS of patients with ER-positive breast cancer. The prognostic significance of HER2-low or HER2-zero status in luminal A- and B-like breast cancers might differ, and a new treatment strategy is required for the HER2-low subgroup.

Identification of risk factors of EGFR-TKIs primary resistance in lung adenocarcinoma patients and construction of a risk predictive model: a case-control study.

Background: Lung cancer is one of the malignancies with the highest incidence and mortality rates. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line treatment for patients with EGFR-mutated lung adenocarcinoma (LUAD). However, some patients with EGFR-sensitive mutations develop primary resistance to EGFR-TKIs. This study aims to analyze the clinical characteristics of LUAD patients with primary resistance to EGFR-TKIs, identify independent risk factors for primary resistance, and establish a risk predictive model to provide reference for clinical decision-making. Methods: We collected data from LUAD patients with EGFR-sensitive mutations (19del/21L858R) who were hospitalized in our institution between 2020 and 2022 and received first-generation EGFR-TKIs with follow-up exceeding 6 months. These patients were categorized into primary resistance and sensitive groups based on treatment outcomes. We compared general clinical data, laboratory tests, and tumor-related characteristics between the two groups, analyzed risk factors for primary resistance to EGFR-TKIs, and constructed a risk predictive model. The model's predictive value was comprehensively assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curves. Results: Serum neuron-specific enolase (NSE) concentration (P=0.03), serum pro-gastrin-releasing peptide (ProGRP) concentration (P=0.01), and Ki67 expression (P<0.001) were identified as independent risk factors for primary resistance to EGFR-TKIs in LUAD. The combined presence of these three risk factors had the highest predictive value [area under the curve (AUC) =0.975, P<0.001]. We constructed a predictive model for the risk of primary resistance to EGFR-TKIs in LUAD patients, incorporating these three parameters, and represented it through a visually interpretable nomogram. The calibration curve of the nomogram demonstrated its strong predictive ability. Further decision curve analysis indicated the model's clinical utility. Conclusions: Based on a single-center retrospective case-control study, we identified serum NSE concentration, ProGRP concentration, and Ki67 expression as independent risk factors for primary resistance to EGFR-TKIs in LUAD patients. We constructed and validated a risk predictive model based on these findings. This predictive model holds promise for clinical application, aiding in the development of personalized treatment strategies and providing a scientific basis for early identification of primary resistance patients.

Erythema dyschromicum perstans-like eruptions induced by epidermal growth factor receptor inhibitors in patients with lung cancer.

INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

PURPOSE: Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. METHODS: We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). RESULTS: 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8 months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. CONCLUSION: This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation.

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

Potential of targeting signal-transducing adaptor protein-2 in cancer therapeutic applications.

Adaptor proteins play essential roles in various intracellular signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that possesses pleckstrin homology (PH) and Src homology 2 (SH2) domains, as well as a YXXQ signal transducer and activator of transcription 3 (STAT3)-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (BRK). STAP-2/BRK expression is deregulated in breast cancers and enhances STAT3-dependent cell proliferation. In prostate cancer cells, STAP-2 interacts with and stabilizes epidermal growth factor receptor (EGFR) after stimulation, resulting in the upregulation of EGFR signaling, which contributes to cancer-cell proliferation and tumor progression. Therefore, inhibition of the interaction between STAP-2 and BRK/EGFR may be a possible therapeutic strategy for these cancers. For this purpose, peptides that interfere with STAP-2/BRK/EGFR binding may have great potential. Indeed, the identified peptide inhibitor successfully suppressed the STAP-2/EGFR protein interaction, EGFR stabilization, and cancer-cell growth. Furthermore, the peptide inhibitor suppressed tumor formation in human prostate- and lung-cancer cell lines in a murine xenograft model. This review focuses on the inhibitory peptide as a promising candidate for the treatment of prostate and lung cancers.

Efficacy and safety of neoadjuvant therapy for HR-positive/HER2-negative early breast cancer: a Bayesian network meta-analysis.

BACKGROUND: Neoadjuvant treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is controversial and requires a comprehensive analysis for optimal therapy assessment. Therefore, a two-step Bayesian network meta-analysis (NMA) was performed to compare the efficacy and safety of different neoadjuvant regimens. RESEARCH DESIGN AND METHODS: Phase II/III randomized clinical trials comparing various neoadjuvant therapies for HR+/HER2- breast cancer were included. NMA and pairwise meta-analyses were conducted using Stata (version 14), R (version 4.2.3), and Review Manager 5.4. RESULTS: Twenty-eight studies (5,625 patients) were eligible. NMA of objective response rate (ORR) indicated the highest SUCRA for chemotherapy (CT) and chemotherapy with anthracycline (CT(A)). Pathologic complete response (PCR) NMA demonstrated significant PCR improvement with chemotherapy regimens containing programmed cell death protein-1 and programmed cell death ligand-1 inhibitors (PD-1i/PD-L1i) and poly ADP-ribose polymerase inhibitors (PARPi). Combined analysis considering both the ORR and safety highlighted CT(A)'s efficacy and toxicity balance. CONCLUSIONS: CT(A) and CT showed improved ORR compared with alternative regimens. CT(A) combined with PD-1/PD-L1 or PARP inhibitors significantly increased PCR rates. Comprehensive assessment of both ORR and safety indicated that CT(A) represents an optimal neoadjuvant therapy for HR+/HER2- breast cancer, whereas AI + CDK4/6 inhibitors rank solely behind chemotherapy. REGISTRATION: PROSPERO Registration: CRD42024538948. International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) registration number INPLASY202440092.

Challenges in HER2-low breast cancer identification, detection, and treatment.

Recently, human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) has emerged as a novel subset within the category of HER2-negative BC, prompting a reassessment of the immunohistochemical negative scores of 0, 1+, and the 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have provided compelling evidence of the substantial clinical advantages offered by novel antibody-drug conjugates (ADCs) that target HER2 in the treatment of these specific tumor cohorts. Notably, trastuzumab deruxtecan (T-Dxd), an ADC that specifically targets HER2, has recently received approval from the US Food and Drug Administration as the inaugural targeted therapeutic option for HER2-low BC. However, the classification of HER2-low BC as a distinct subtype, the methods for detecting HER2-low BC, and the optimal treatment approach for HER2-low BC remain subjects of ongoing debate and lack consensus. This comprehensive review aims to address these pertinent concerns, offering insights into the nuanced tumor biology underlying HER2-low BC and critically analyzing the current treatment pathways available. By synthesizing available evidence, the objective is to contribute to an enhanced understanding of HER2-low BC, providing a foundation for more informed clinical decisions and further advancements in tailored therapeutic approaches. As the medical community navigates these uncertainties, this review seeks to consolidate existing knowledge, fostering a collective effort toward establishing consensus in the diagnosis and treatment of HER2-low BC.

Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.

Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.

Predicting human epidermal growth factor receptor 2 status of patients with gastric cancer by computed tomography and clinical features.

Background: There have been no studies on predicting human epidermal growth factor receptor 2 (HER2) status in patients with resectable gastric cancer (GC) in the neoadjuvant and perioperative settings. We aimed to investigate the use of preoperative contrast-enhanced computed tomography (CECT) imaging features combined with clinical characteristics for predicting HER2 expression in GC. Methods: We retrospectively enrolled 301 patients with GC who underwent curative resection and preoperative CECT. HER2 status was confirmed by postoperative immunohistochemical analysis with or without fluorescence in situ hybridization. A prediction model was developed using CECT imaging features and clinical characteristics that were independently associated with HER2 status using multivariate logistic regression analysis. Receiver operating characteristic curves were constructed and the performance of the prediction model was evaluated. The bootstrap method was used for internal validation. Results: Three CECT imaging features and one serum tumor marker were independently associated with HER2 status in GC: enhancement ratio in the arterial phase (odds ratio [OR] = 4.535; 95% confidence interval [CI], 2.220-9.264), intratumoral necrosis (OR = 2.64; 95% CI, 1.180-5.258), tumor margin (OR = 3.773; 95% CI, 1.968-7.235), and cancer antigen 125 (CA125) level (OR = 5.551; 95% CI, 1.361-22.651). A prediction model derived from these variables showed an area under the receiver operating characteristic curve of 0.802 (95% CI, 0.740-0.864) for predicting HER2 status in GC. The established model was stable, and the parameters were accurately estimated. Conclusions: Enhancement ratio in the arterial phase, intratumoral necrosis, tumor margin, and CA125 levels were independently associated with HER2 status in GC. The prediction model derived from these factors may be used preoperatively to estimate HER2 status in GC and guide clinical treatment.