Cancer最新文献

Endocrine therapy following breast-conserving surgery in older women with low-risk, early-stage breast cancer was associated with a greater reduction in health-related quality of life (HRQOL) than radiation therapy according to the interim analysis of the EUROPA trial presented at the San Antonio Breast Cancer Symposium¹ and published in The Lancet Oncology.²

The EUROPA trial is a noninferiority, phase 3 study in which 731 women (with a final accrual target of 926 patients) aged 70 years or older with stage I, luminal A–like breast cancer were randomized to a single-modality treatment with either radiotherapy (n = 365) or endocrine therapy (n = 366). The study compared the effects on HRQOL and ipsilateral breast tumor recurrence. Changes in HRQOL from the baseline to 2 years were assessed with the global health status scale of the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.

Results of the preplanned interim analysis, which included 207 patients (104 received radiotherapy, and 103 received endocrine therapy), showed a significant reduction in HRQOL in the patients treated with endocrine therapy versus radiotherapy.

At 2 years, patients treated with endocrine therapy had a mean change from the baseline in global health status of –9.79 (95% CI, –14.45 to –5.13; p < .0001), whereas the mean change for those treated with radiotherapy was –3.40 (95% CI, –7.82 to 1.03; p = .13). The adjusted mean difference between the treatments was 6.39 (95% CI, 0.14–12.65; p = .04), with radiotherapy favored.

Patients treated with radiotherapy also had less frequent treatment-related adverse events than those treated with endocrine therapy (67% vs. 85%). The most common grade 3–4 adverse events were experienced by patients in the endocrinology group (none in the radiotherapy group) and included arthralgia (7%), pelvic organ prolapse (3%), fatigue/hot flashes/myalgia (2%), and bone pain/fractures (2%). Serious adverse events were similar between the two treatment groups.

The lead author of the study, Icro Meattini, MD, an associate professor in the Department of Experimental and Clinical Biomedical Sciences “M. Serio” at the University of Florence in Italy, says that the study shows that single-modality therapy has promise as a noninferior alternative to endocrine therapy for improved HRQOL.

“These findings highlight the potential for personalized treatment approaches that align with patient preferences, comorbidities, and treatment tolerability,” he says, adding that the findings “could influence shared decision-making and reduce overtreatment in a subset of older patients with favorable tumor biology.”

Although the interim results are encouraging, he says that the trial will continue as planned to ensure a robust data set for the final analysis.

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC). The development of selective, covalent KRAS G12C (KRAS^G12C) inhibitors represents a breakthrough in the treatment for KRAS^G12C mutant NSCLC, but the durability of response and efficacy of these inhibitors are limited by the rapid emergence of drug resistance and their ability to only bind KRAS^G12C in the guanosine diphosphate-bound form. Importantly, co-occurring gene alterations, including KEAP1, STK11, and CDKN2A, may affect prognosis and response to therapies, including immunotherapy and KRAS^G12C inhibitors. New therapeutic approaches are needed to both delay and overcome treatment resistance. Moreover, developing KRAS inhibitors with novel mechanisms of action and alternative allele specificities is necessary to overcome emerging on-target resistance mechanisms to KRAS^G12C inhibitors. A literature search was performed using PubMed, the Food and Drug Administration website, and Google search. The inclusive dates in the literature search were between 1982 and July 2024. In this article, the authors reviewed the disease prevalence, biology and therapeutic options, including specific KRAS^G12C inhibitors and new pan-KRAS therapeutic agents for KRAS^G12C mutant NSCLC. KRAS inhibitor resistance mechanisms, treatment strategies, and multi-targeted treatment approaches are also discussed.

Lung cancer is the leading cause of cancer death worldwide. However, since the discovery and development of targeted therapies and immune checkpoint inhibitors, it has been a dramatically improved in survival outcomes and quality of life. Anaplastic lymphoma kinase (ALK) rearrangements occur in approximately 5% of patients with advanced non–small cell lung cancer (NSCLC), and the introduction of ALK tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm. Although head-to-head randomized controlled trials for late generation inhibitors are lacking, the authors will review the current available options, treatments efficacy, safety profiles, ALK mechanisms of resistance, as well as new promising treatments in this field.

Multicancer early detection (MCED) tests are an emerging technology for cancer screening. MCED tests can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. Some tests can suggest the most likely cancer origin, whereas others report cancer detected somewhere in the body. Although some MCED tests are currently commercially available, none are approved by the Food and Drug Administration or endorsed by any clinical practice guideline or recommendation. Most insurance companies do not currently cover MCED testing. MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials. Because patients already are asking for MCED test prescriptions or for interpretation of results from tests acquired elsewhere, clinicians should be prepared to discuss what is known about the benefits, risks, and uncertainties of MCED testing, including performance characteristics in screening populations and preferred follow-up strategies for positive test results. At this time, clinicians should not feel obligated to initiate discussions about MCED testing with their patients. However, clinicians should engage patients who inquire about getting tested or previous MCED test results in shared decision-making, and take the opportunity to offer and help patients complete age- and sex-appropriate guideline-recommended cancer screenings. In this article, the current evidence and issues around MCED testing are summarized, and a framework for shared decision-making discussions is provided.

ERBB2 (HER2) alterations, including mutations, amplifications, and overexpression are emerging therapeutic targets in non–small cell lung cancer (NSCLC). Despite recent advancements, standard first-line therapy remains chemotherapy with or without immunotherapy. Several therapies targeting HER2 are under development and have been evaluated in clinical trials with inconsistent efficacy, including monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates. A major landmark was recently reached when trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate, became the first Food and Drug Administration (FDA)-approved therapy for pretreated HER2-mutant NSCLC, following the promising efficacy demonstrated in the DESTINY-Lung trials. Furthermore, T-DXd has shown efficacy across various tumor types harboring HER2 alterations in the DESTINY-PanTumor trials, leading to its recent pan-tumor FDA approval for HER2-positive solid tumors, highlighting the potential of tumor-agnostic drug development strategies. In this review, the authors describe the different HER2 alterations and their clinical consequences, including their impact on prognosis and response to standard therapies. They provide an up-to-date overview of the current treatment landscape and add a comprehensive review of pivotal and ongoing clinical trials of HER2-targeted therapies, including tumor-agnostic drug development strategies.

V-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations are found in up to 4% of patients with non–small cell lung cancer (NSCLC). Approximately 2% of advanced NSCLC cases harbor a BRAF V600E (class I) mutation. Because targeted therapies inhibiting BRAF (e.g., dabrafenib and encorafenib) and MEK (trametinib and binimetinib) are associated with improved outcomes as first- or second-line treatment for BRAF V600E–mutant NSCLC, both European Society for Medical Oncology and National Comprehensive Cancer Network guidelines recommend testing for the BRAF V600E oncogenic driver at the time of diagnosis. In recent years, the treatment landscape of this molecular subgroup has seen great development. Different therapeutic strategies including anti–programmed death ligand 1 antibodies and kinase inhibitors have been assessed thus far, with novel agents (e.g., pan-BRAF inhibitors) and therapeutic associations underway in preclinical and clinical trials. This review describes the current understanding of the BRAF clinicopathologic role in NSCLC, with a special focus on published trials assessing currently approved therapies. Mechanisms of drug resistance and future perspectives on the therapeutic approach of BRAF-deregulated NSCLC are also summarized.

ROS1 rearrangements define a molecular subset of non–small cell lung cancer (NSCLC) by accounting for 1%–2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%–70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood–brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life.