Epidermal Growth Factor Receptor (EGFR) targeted therapies have yielded variable results in clinical trials for breast and head and neck cancers, despite EGFR overexpression in these malignancies. Primary resistance to t...Epidermal Growth Factor Receptor (EGFR) targeted therapies have yielded variable results in clinical trials for breast and head and neck cancers, despite EGFR overexpression in these malignancies. Primary resistance to these therapies is common, with secondary resistance often arising due to the overexpression of other receptor tyrosine kinases (RTKs) and increased downstream signaling from these RTKs. Additionally, non-RTK-driven mechanisms also contribute to anti-EGFR therapy resistance. This review highlights the role of AXL, MET, and RON families of RTKs in tumor progression and resistance to anti-EGFR therapies, focusing on breast and head and neck cancers. In breast cancer, the review discusses the intricate relationship between EGFR expression and therapeutic outcomes, emphasizing the challenges and potential strategies for enhancing EGFR-targeted treatments. It details how EGFR inhibition affects tumor progression and survival in head and neck cancer, noting that small molecule inhibitors and monoclonal antibodies, such as cetuximab, can lead to trans-activation of other RTKs. The review further explores non-RTK-driven resistance mechanisms in breast cancer, including EGFR activation through EGF-related ligands, nuclear localization of EGFR, and the overexpression of resistance-conferring proteins. In head and neck cancer, resistance is also mediated by TLR4-MyD88 signaling activation, loss of tumor suppressor genes like PTEN, activating mutations in PI3K, and involvement of STAT3. By synthesizing current insights on both RTK and non-RTK mediated resistance against anti-EGFR therapies, this review aims to guide future research and improve therapeutic strategies for these cancers.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with poorly characterized molecular features. To identify disease-specific mutational profiles, we performed targeted next-generatio...Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with poorly characterized molecular features. To identify disease-specific mutational profiles, we performed targeted next-generation sequencing (NGS) on a cohort of 21 BPDCN patients. Our study revealed that (57%) and (33%) were the most frequently mutated genes, followed by (29%), (14%), (14%), and (14%). Further analysis demonstrated that poor prognosis was associated with older age (≥65 years), the presence of three or more mutations, mutations, truncating mutations, and mutations involving DNA methylation pathways. In contrast, patients who underwent hematopoietic stem cell transplantation (HSCT) exhibited more favorable clinical outcomes. Moreover, our study indicated that expression was significantly elevated in BPDCN cases compared to those with acute myeloid leukemia (AML) or chronic monomyelocytic leukemia (CMML), suggesting that may serve as a reliable diagnostic marker for distinguishing BPDCN from AML, as well as a potential biomarker for disease monitoring. Finally, our investigation of mutational profiles in sequentially paired specimens revealed a high prevalence of bone marrow clonal hematopoiesis in patients with BPDCN. In conclusion, the genetic landscape of BPDCN identified in this study provides valuable insights that may improve diagnostic accuracy and guide prognostic evaluation and therapeutic strategies. However, validation in larger, independent cohorts are warranted.
Often associated with a poor prognosis, advanced urothelial carcinoma (aUC) has progressed to muscle-invasive or metastatic stages. Traditionally, chemotherapy has been the primary treatment for aUC, though its effective...Often associated with a poor prognosis, advanced urothelial carcinoma (aUC) has progressed to muscle-invasive or metastatic stages. Traditionally, chemotherapy has been the primary treatment for aUC, though its effectiveness in advanced stages remains limited. Recent developments have introduced promising therapies, notably the combination of enfortumab vedotin with pembrolizumab, which is now recommended as the first-line therapy following the EV-302 trial results. This combination has demonstrated significant improvements in survival rates. This review aims to explore the evolution of treatment strategies for aUC, emphasizing the shift towards immunotherapy and targeted therapies, and discusses the potential for optimized treatment algorithms to improve patient outcomes.
Heavily pretreated metastatic colorectal cancer (mCRC) poses significant therapeutic challenges. Advances in molecular profiling enables personalized strategies. We present a 62-year-old male with mCRC harboring , , , a...Heavily pretreated metastatic colorectal cancer (mCRC) poses significant therapeutic challenges. Advances in molecular profiling enables personalized strategies. We present a 62-year-old male with mCRC harboring , , , and alterations, following FOLFOX and FOLFIRI, dabrafenib plus panitumumab, and a BRAF inhibitor clinical trial, each leading to initial responses followed by disease progression. WIN Consortium International Molecular Tumor Board (MTB), included experts from institutions across 13 countries. Enrollment in suitable clinical trials was explored but limited by availability. Personalized combinations suggested included amivantamab-vmjw (anti-MET/EGFR antibody) (one-third standard dose) (for MET amplification and due to prior response to anti-EGFR antibody), trametinib, 1 mg po daily (MEK inhibitor for mutation), and regorafenib (may have WNT inhibitor activity relevant to mutation; VEGFR activity relevant since alterations upregulate VEGF/VEGFR axis) starting at 40 mg po daily three weeks on, one week off. Another option was trametinib at 1 mg daily, cetuximab (EGFR antibody), 250 mg/m² IV every two-weeks, and cabozantinib (MET and VEGFR inhibitor), 40 mg po daily. FOLFOXFIRI combined with bevacizumab, or liver-directed therapies for hepatic metastases, or regorafenib with 5FU, or crizotinib (MET inhibitor) combined with regorafenib or dabrafenib, was also suggested. This case emphasizes the critical role of comprehensive molecular profiling and personalized therapeutic approaches in managing complex mCRC. The WIN International MTB aims to provide treatment and biomarker analysis discussion with the ultimate goal of optimizing treatment efficacy by targeting specific molecular alterations, though final treatment decisions remain at the discretion of the treating physician.
HER2 genomic alterations characterize a specific subset of NSCLC with potential therapeutic relevance. While most studies focus on populations from high-income countries, data from Latin America remains scarce. We retros...HER2 genomic alterations characterize a specific subset of NSCLC with potential therapeutic relevance. While most studies focus on populations from high-income countries, data from Latin America remains scarce. We retrospectively analyzed 13 HER2-mutated NSCLC cases from a single institution in Northeastern Brazil, integrating clinical, histopathological, immunohistochemical, and molecular findings. Predominant histological patterns included acinar and lepidic subtypes, with HER2 mutations primarily involving exon 20 insertions (A775_G776insYVMA) and frequent co-alterations in TP53, KRAS, and STK11. HER2 protein expression assessed by IHC showed low scores (0-2+) in most cases, while HER2 gene amplification was confirmed in one case by D-DISH and NGS. Tumor mutation burden was universally low. Treatment responses varied, with one patient receiving trastuzumab deruxtecan. Our findings highlight the molecular diversity and diagnostic challenges of HER2-mutated NSCLC in underrepresented populations, emphasizing the need for comprehensive molecular profiling and expanded access to targeted therapies.
The gene serves a canonical role in the DNA damage response (DDR) pathway encoding the regulatory kinase CHK2 in the homologous recombination (HR) repair of double-strand breaks (DSB). Although is traditionally conside...The gene serves a canonical role in the DNA damage response (DDR) pathway encoding the regulatory kinase CHK2 in the homologous recombination (HR) repair of double-strand breaks (DSB). Although is traditionally considered a tumor suppressor gene, recent studies suggest additional functions. Across several cohort studies, expression was negatively correlated with the efficacy of immune checkpoint inhibitors (ICI), which target the interaction between effector immune and tumor cells. This review explores two possible explanations for this observed phenomenon: the first relating to the canonical role of , and the second introducing a novel role of the gene in immunomodulation of the tumor microenvironment (TME). DDR mutations have been implicated in increased levels of tumor mutation burden (TMB), often manifesting as neoepitope expression on the tumor cell surface recognized by effector immune cells. As a result, impaired DNA repair due to loss of function, either from germline deleterious variants or acquired mutations, results in the recruitment of CD8+ cytotoxic T-cells and subsequent efficacy of ICI treatment. However, functional loss of may be directly involved in potentiating the immune response through canonical inflammatory and anti-tumor pathways, acting through the cGAS-STING pathway. Although the exact mechanism by which modulates immune responses is still under investigation, combination therapy with CHEK1/2 inhibition and ICI immunotherapy has shown benefit in preclinical studies of several solid tumors.
INTRODUCTION: Immunotherapy has emerged as a standard treatment option for multiple solid tumors. However, most patients with pancreatic cancer (PC) do not derive a significant benefit. Identification and analyses of exc...INTRODUCTION: Immunotherapy has emerged as a standard treatment option for multiple solid tumors. However, most patients with pancreatic cancer (PC) do not derive a significant benefit. Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy. METHODS: Oncologists from cancer centers in the United States were contacted to identify patients with PC who responded to immunotherapy. Exceptional responders were defined as those having either partial (PR) or complete response (CR) based on Response Evaluation Criteria in Solid Tumors, or biochemical response (CA 19-9 levels) after starting immunotherapy. Patients receiving concurrent chemotherapy were excluded. RESULTS: 14 patients met inclusion criteria. Immunotherapy drugs included checkpoint inhibitors and macrophage inhibitors. Eight patients (42%) were MSI (microsatellite instability)-high. Radiologically, 82% had PR. Four patients (28%) had marked reduction in CA 19-9. The median progression-free survival was 12 months from the start of immunotherapy. Median survival was not reached. The 1- and 2-year survival probabilities were 80%, 70% respectively. CONCLUSION: Majority of clinical trials evaluating immunotherapy in PC have yielded disappointing response rates compared to other solid tumors. Our case series adds to published data from early-phase trials supporting the promise of immunotherapy in some patients with PC.
Vergani E, Guardo LD, Dugo M
… +18 more, Rigoletto S, Tragni G, Ruggeri R, Perrone F, Tamborini E, Gloghini A, Arienti F, Vergani B, Deho P, Cecco L, Vallacchi V, Frati P, Shahaj E, Villa A, Santinami M, Braud F, Rivoltini L, Rodolfo M
The unattainable triangle, also known as the iron triangle or triple constraint, traditionally applied in business as a model for balancing time, cost, and quality, offers valuable insight into the field of cardio-oncolo...The unattainable triangle, also known as the iron triangle or triple constraint, traditionally applied in business as a model for balancing time, cost, and quality, offers valuable insight into the field of cardio-oncology. Cardio-oncology merges cardiovascular care with cancer treatment, addressing the growing risk of cardiovascular complications in cancer patients. Similar to the business model, this specialty faces the challenge of providing timely, high-quality, and cost-effective care. The urgency of cancer treatment often strains cardiovascular assessments, while comprehensive care increases costs due to advanced diagnostics and specialized teams. Establishing a cardio-oncology center of excellence, where oncologists and cardiologists collaborate in real-time, can help balance these demands, enhance care coordination, and manage resource utilization effectively. This article explores how the specialty of cardio-oncology could deliver comprehensive, timely, and affordable patient care by applying the unattainable triangle method.
Patients with NSCLC harboring uncommon EGFR mutations have limited therapeutic options and often poor outcomes, especially following progression on standard EGFR tyrosine kinase inhibitors (TKIs). Amivantamab, an anti-EG...Patients with NSCLC harboring uncommon EGFR mutations have limited therapeutic options and often poor outcomes, especially following progression on standard EGFR tyrosine kinase inhibitors (TKIs). Amivantamab, an anti-EGFR/MET bispecific antibody, shows efficacy in EGFR-mutated NSCLC, but its role in rare EGFR alterations and CNS involvement, including leptomeningeal disease (LMD), remains insufficiently characterized. We report a 67-year-old male with stage IVB NSCLC harboring EGFR G719A and A289V mutations who developed LMD while on osimertinib. After progression on immunotherapy and chemotherapy, amivantamab monotherapy was initiated. Treatment produced a durable response over 19 months, including a 32.2% reduction in tumor size at six weeks, and complete resolution of brain metastases and LMD by six months. Circulating tumor DNA analyses showed EGFR variant allele fractions decreasing from 25.6% to undetectable. This case challenges current paradigms, demonstrating that amivantamab monotherapy can effectively target rare EGFR mutations, achieve durable extracranial and CNS disease control, and potentially overcome blood-brain barrier limitations. These findings suggest that amivantamab's utility may extend beyond established combination regimens and well-characterized EGFR mutations, offering an effective option for patients with atypical molecular profiles who lack standard therapies. Amivantamab monotherapy may represent a viable strategy for patients with uncommon EGFR mutations and CNS involvement, including LMD. Further research is warranted to elucidate underlying mechanisms, refine treatment strategies, and assess amivantamab's broader applicability in similarly challenging NSCLC scenarios.
We previously showed that proliferating cell nuclear antigen (PCNA) interacts with androgen receptor (AR) through a PIP-box (PIP-box4) at the N-terminus of AR and regulates AR activity. In this study, we further investig...We previously showed that proliferating cell nuclear antigen (PCNA) interacts with androgen receptor (AR) through a PIP-box (PIP-box4) at the N-terminus of AR and regulates AR activity. In this study, we further investigated PCNA/AR interaction. We identified a second PIP-box (PIP-box592) in the DNA binding domain of AR and found that dihydrotestosterone enhances the binding of full-length AR (AR-FL) but not a constitutively active variant (AR-V7) to PCNA. Treatment with R9-AR-PIP, a PIP-box4-mimicking small peptide, inhibits the PCNA/AR interaction, AR occupancy at the androgen response element (ARE) in and genes, and expression of AR target genes, and induces cytotoxicity in AR-positive castration-resistant prostate cancer (CRPC) cells. R9-AR-PIP also significantly inhibits transcriptional activity of AR-FL upon dihydrotestosterone stimulation and the constitutive activity of AR-V7. Moreover, R9-AR-PIP and PCNA-I1S, a small molecule PCNA inhibitor, inhibit the ARE occupancy by AR-FL and AR-Vs in gene that encodes cyclin A2 and cyclin A2 expression. Finally, we found that cyclin A2 is overexpressed in all CRPC cells examined, suggesting that it may contribute to the development of CRPC. These data indicate that targeting PCNA/AR interaction inhibits both AR-FL- and AR-Vs-mediated signaling and implicates it could be a novel therapeutic strategy against CRPC.
Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely underst...Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a "double hit" mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response.
da Fonseca LG, Piñero F, Anders M
… +17 more, Bermudez C, Demirdjian E, Varón A, Perez D, Rodriguez J, Beltrán O, Ridruejo E, Caballini P, Araujo A, Florez JDT, Marín JI, Villa M, Orozco F, Poniachik J, Marciano S, Bessone F, Mendizabal M
AIMS: Latin America has been underrepresented in trials evaluating immunotherapy for hepatocellular carcinoma (HCC). We aimed to describe the incidence of immune-related adverse events (irAEs) and their impact on outcome...AIMS: Latin America has been underrepresented in trials evaluating immunotherapy for hepatocellular carcinoma (HCC). We aimed to describe the incidence of immune-related adverse events (irAEs) and their impact on outcomes in a Latin American cohort. METHODS: A multicenter prospective study was conducted in Argentina, Brazil, Chile, and Colombia, including patients who received atezolizumab plus bevacizumab. A time-covarite proportional hazard analysis evaluated the effect of irAEs. RESULTS: 99 patients were included. The median treatment duration was 6 months, with a median survival of 17.0 months (95% CI: 12.6-19.8). The irAE incidence rate was 2.1 cases per 100 persons-months (cumulative incidence 18.1% (95% CI: 11.1-27.2%)). Median time to irAE was 2.3 months (range 1.4-4.8), most frequently hepatitis ( = 6), thyroiditis ( = 5), and 8/18 required steroids. Follow-up, treatment duration, and overall survival were similar regardless of the occurrence of irAEs (HR = 1.71, 95% CI: 0.76-3.86; = 0.19). Baseline alpha-feto protein ≥400 ng/ml (HR: 2.9 (95% CI: 1.1-7.6)) was independently associated with irAE. CONCLUSION: The incidence of irAEs in this cohort is lower than reported in controlled trials, withouut impact on survival outcomes. Education and early recognition are crucial to ensure that these events are identified and addressed.