Hampig Raphael Kourie

1. Gastrointestinal (GI) cancers account for 28.62% of global cancer incidence and 43% of all cancer-related deaths in 2022 [1]. Their rising incidence, particularly among young adults, underscores...

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) represents a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with the SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward molecularly selected combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in acquired resistance. Multiple randomized studies have demonstrated that adding targeted agents to endocrine therapy improves progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression, except in carefully selected patients with low disease burden, indolent biology, or frailty where tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. Real-world analyses further support the effectiveness of these biomarker-directed strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms, including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which may co-occur and reduce sensitivity to endocrine monotherapy. While ESR1 and PI3K pathway alterations now guide approved therapies, FGFR alterations remain investigational targets, with ongoing trials evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can detect emergent ESR1 mutations before radiographic progression, providing a clinically actionable lead time for early therapeutic modification and extending endocrine-based disease control by approximately 5 to 7 months. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC.

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) remains a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib (for PIK3CA-mutated tumors), established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in the setting of acquired resistance. Multiple randomized studies have demonstrated that the addition of targeted agents to endocrine therapy results in significantly improved progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression. Current evidence strongly supports that in hormone receptor–positive metastatic breast cancer progressing after CDK4/6 inhibitors, combination therapy with endocrine agents and targeted treatments should be favored over single-agent hormonal therapy, except in carefully selected patients with low disease burden, indolent biology, or frailty where treatment tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib demonstrated significant benefit when combined with fulvestrant in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. These findings consistently reinforce that endocrine therapy combined with pathway-targeted agents provides superior clinical outcomes compared with endocrine therapy alone, particularly in patients previously treated with CDK4/6 inhibitors. Real-world analyses further confirm the effectiveness of these combination strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which frequently co occur in up to one third of tumors and contribute to reduced sensitivity to endocrine monotherapy, further emphasizing the importance of combination treatment strategies. Notably, while ESR1 and PI3K pathway alterations guide approved therapies, FGFR alterations remain early-phase targets without integrated standard-of-care options, though ongoing trials are evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can guide early therapeutic modification, extending endocrine-based disease control by approximately 5 to 7 months when ESR1 mutations are detected prior to radiographic progression. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC.

This study aims to update the mutational status of EGFR in non-small cell carcinoma (NSCLC), to analyze the spectrum of mutations found, and describe rare

Escalated BEACOPP has long been a key component in the treatment of Hodgkin lymphoma, offering significant survival benefits in both early and advanced stages. However, its use comes with considerable drawbacks, including heightened toxicity, infertility, and an increased risk of secondary malignancies. The emergence of novel therapies, such as Brentuximab Vedotin—an anti-CD30 antibody-drug conjugate—and immune checkpoint inhibitors like Nivolumab and Pembrolizumab, has begun to redefine the treatment landscape. These advancements provide comparable or superior efficacy while significantly reducing toxicity. This article examines the gradual decline of escalated BEACOPP in Hodgkin lymphoma treatment, highlighting recent clinical trial data and evolving therapy protocols that are shifting treatment paradigms. Additionally, it explores updates in international guidelines reflecting these changes. Despite the promise of newer therapies, their widespread adoption presents challenges, including accessibility, cost, and long-term efficacy considerations. This review discusses these hurdles while looking ahead to future directions in Hodgkin lymphoma management.

Osteosarcoma is the most common malignant bone tumor in children and adolescents, characterized by high heterogeneity and a complex tumor microenvironment (TME). Despite multimodal treatments, survival rates have stagnated, highlighting the need for new therapeutic options. Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect heterogeneity and uncover mechanisms of progression and immune evasion. A narrative literature review, guided by PRISMA principles, was conducted through October 2024 via PubMed and Scopus databases to assess scRNA-seq contributions to osteosarcomagenesis. A total of 107 studies were analyzed to highlight the identification of tumor subpopulations, signaling pathways, diagnostic and prognostic biomarkers, and therapeutic assessments. Our analysis highlights the critical role of scRNA-seq in revealing the complexity of the osteosarcoma TME. Studies identified distinct immune and non-immune cell subpopulations, with TXNIP+ and IFIT1+ macrophages, KAZALD1, EGFL7, TNFSF11, and TRAIL receptors emerging as potential therapeutic targets. scRNA-seq has elucidated mechanisms of tumor progression and metastasis, including CD24 expression, and enabled the discovery of immune and stromal biomarkers within the TME. It also revealed novel therapeutic strategies, such as targeting Tregs via CXCR4 inhibition, CAFs through LOX and SERPINE1 modulation, and MCL1 in metastatic niches. Additionally, it uncovered promising drug candidates—etoposide, mevastatin, oxfendazole, HDAC inhibitors, and TIGIT blockade—as well as immunotherapies like PD-1 inhibition and adoptive CD8+ T cell therapy. scRNA-seq has transformed insights into osteosarcoma by exposing key cellular dynamics and potential therapeutic targets. While technical challenges remain, it paves the way for more personalized and effective treatment strategies. However, the current findings are subject to limitations, including technical biases in single-cell protocols and the exclusion of non-English literature, which may affect generalizability.

Lung cancer is the leading cause of cancer-related death and the second most common cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. In the Middle East and North Africa (MENA) region, lung cancer ranks second in incidence and cancer mortality, with a five-year survival rate of about 8%. To address this pressing health challenge, this expert consensus aims to provide regionally tailored recommendations to improve outcomes for patients with advanced NSCLC in the MENA region. A panel of 15 regional experts convened to develop evidence-informed guidance using a modified Delphi process. Through this structured and collaborative approach, the panel formulated 40 consensus statements covering key areas such as epidemiology, diagnostic workup, molecular testing, and the use of targeted therapies in advanced NSCLC. These statements reflect both global best practices and region-specific considerations, including access to testing and treatment. The resulting recommendations offer the first regionally adapted framework for the management of advanced NSCLC in the MENA region. By unifying clinical practice and promoting precision medicine, these guidelines aim to support clinicians in improving patient care and outcomes across the region.

Cancer dormancy poses a major challenge in oncology, often leading to relapse and metastasis years after initial treatment. This phenomenon is driven by the ability of dormant cancer cells to evade immune detection and resist chemotherapy. Thus, these cells remain in a quiescent state until conditions favor their reactivation. A deeper understanding of the mechanisms governing dormancy—including cellular signaling pathways, the role of the tumor microenvironment, and immune system interactions—is essential for developing effective and practical therapeutic interventions. Recent research has highlighted three primary strategies for targeting dormant breast cancer cells: the killing strategy, the sleeping strategy, and the awakening strategy. This review explores the various techniques used to detect dormant breast cancer cells and evaluates experimental therapeutic approaches aimed at either eradicating or controlling them. By synthesizing the latest advancements in cancer dormancy research, this article provides valuable insights for oncologists while remaining accessible to a broader audience.