Abstract Step therapy ("fail-first") policies require patients to initiate treatment with a payer-preferred regimen, often selected for cost, before coverage is granted for the oncologist-recommended therapy. In medical oncology, where biologic heterogeneity, biomarker-directed therapy, and time-sensitive sequencing determine outcomes, step edits can function as an avoidable barrier to evidence-based care. We performed a narrative review of peer-reviewed literature (2010-2025) and relevant U.S. regulatory and policy documents to summarize the clinical, economic, and equity implications of step therapy as applied to systemic anticancer treatments. Evidence from cancer-specific and cross-cutting utilization management research suggests that coverage restrictions can delay initiation or continuation of therapy and increase treatment discontinuation. We synthesize mechanisms of harm (time-to-treatment delays, forced non-guideline-concordant sequencing, and toxicity exposure), describe contemporary case examples across therapeutic areas, and propose actionable policy remedies. Oncology-specific safeguards, including transparent clinical criteria, rapid exceptions and appeals, continuity-of-care protections, and provider performance-based exemptions ("gold-carding"), are essential to balance payer oversight with the imperatives of precision oncology.
Abstract Background Most breast cancer cases in sub-Saharan Africa are diagnosed at advanced stages. The World Health Organization’s Global Breast Cancer Initiative (GBCI) emphasizes early diagnosis and recommends that women with suspicious breast lesions promptly consult a health care provider (HCP) and receive a pathologic diagnosis within 60 days of their initial visit. Patients and Methods We interviewed 194 women undergoing diagnostic evaluation for suspicious breast lesions at a zonal referral hospital in northern Tanzania to assess diagnostic timeliness. Two intervals were examined: the pre-contact interval from first symptom recognition to the initial HCP visit, and the post-contact interval from the first HCP visit to the definitive pathological diagnosis. Negative binomial regression models were applied to assess factors influencing the duration of pre- and post-contact intervals. Results The median pre-contact interval length was 1.0 month (IQR: 0.2–4.7), and the median post-contact interval was 0.9 months (IQR: 0.2–5.5). Overall, 63% of women received a pathological diagnosis within 60 days of first HCP contact, meeting the GBCI benchmark. Consulting multiple HCPs was associated with longer post-contact intervals, whereas being married and referral for pathologic evaluation at initial HCP visit were associated with shorter intervals. Breast cancer was diagnosed in 28% of participants. Conclusion We observed comparatively short diagnostic intervals, with several modifiable factors influencing interval lengths. Targeted training of frontline HCPs and sustained breast cancer awareness efforts are particularly needed for women experiencing prolonged delays from symptom onset to diagnosis. Continued monitoring of diagnostic intervals is essential to sustain and improve diagnostic timeliness.
Abstract Brainstem gliomas (BSG) are rare in adults (less than 2% of all gliomas) and generally have a better prognosis than pediatric BSG, although outcomes remain heterogeneous. Many other central nervous system (CNS) tumors, as well as nontumoral lesions, have been described as differential diagnoses and should be kept in mind. Each case should be examined by neurosurgeons from specialized centers to determine the most appropriate surgical approach among stereotactic biopsy, open biopsy, and tumor resection. Surgery may sometimes be performed in expert centers. The main objectives of tumor tissue sampling are to perform histomolecular analyses to confirm the diagnosis, determine the tumor subtype, and identify potential prognostic and theranostic biomarkers. Tissue preservation is essential to ensure that sufficient tumor material is available for further molecular analyses for diagnostic or therapeutic purposes. Results of ctDNA detection in CSF should only be considered if they are positive. The management of BSGs in adults remains non-standardized, largely because most glioma trials exclude tumors located in this specific site. To date, no prospective trials have established clear treatment guidelines, and most of the available data come from retrospective studies or extrapolation of data from other locations. Radiotherapy (RT) is one of the main treatment options for BSGs in adults. The role of chemotherapy remains unclear due to limited data in literature and is currently being studied. Several molecular targets with therapeutic potential, including recurrent genetic mutations and fusion transcripts, have been identified in adult BSGs.
Abstract Background Despite advances in metastatic androgen pathway modulation-sensitive prostate cancer (mAPMS) treatment, outcomes remain heterogeneous. Achieving a post-treatment undetectable prostate-specific antigen (PSA) is a strong prognostic marker. We aimed to identify genomic and transcriptomic determinants of PSA response in a real-world clinical-genomic cohort. Patients and Methods Patients with mAPMS who underwent DNA (Tempus xT) and, in a subset, RNA (Tempus xR) sequencing were identified from the Tempus Lens database. Inclusion required stage IV disease within 90 days of sample collection and obtained within 12 months before or 3 months after treatment initiation. Patients with PSA at 6 months (n = 525) were classified as PSA-Low (<0.1 ng/mL, n = 240) or PSA-High (≥0.1 ng/mL, n = 285). Overall survival (OS) was assessed by 6-month landmark analysis with delayed-entry adjustment. Logistic and Cox models were adjusted for clinical variables. Sensitivity analyses used a relative definition of >95% PSA decline from baseline. Results Baseline PSA was lower in PSA-Low versus PSA-High patients (24 vs 36 ng/mL, P = .01). SPOP (17% vs 11%) and ZFHX3 (2.5% vs 6%) alterations differed between groups, but neither persisted after adjustment. Using the relative definition, ZMYM3 and JAK1 alterations were independently associated with failure to achieve a deep PSA response. Expression of PSMA, TROP2, B7-H3, and STEAP1 did not differ between groups. PSA-Low status was independently associated with improved OS, as was deep relative response. Conclusion Deep PSA response at 6 months correlates with improved OS in mAPMS. Integrating molecular markers with PSA response may inform treatment intensification or de-escalation strategies.
Abstract Background APEC1621 arm M, a subprotocol of the NCI-COG Pediatric MATCH clinical trial, is a phase 2 study evaluating tipifarnib, a farnesyl transferase inhibitor, in patients with relapsed or refractory solid tumors harboring HRAS mutations at codons G12, G13, Q61, or A146 (NCT04284774). Methods Patients identified by the MATCH screening protocol and enrolled to the arm M subprotocol received tipifarnib at 350 mg/m2/dose (maximum 600 mg/dose) orally twice daily on an intermittent dosing schedule (days 1 to 7 and 15 to 21, every 28 days) until disease progression or intolerable toxicity. The primary aim was to determine the objective response rate (ORR) and secondary objectives included estimating progression-free survival (PFS) and assessing the tolerability of tipifarnib on the intermittent dosing schedule in children. Results Seven patients matched to the tipifarnib subprotocol and five patients (71%) enrolled. Two matched patients were ineligible for treatment. Diagnoses for the enrolled patients were rhabdomyosarcoma (n = 4) and angiosarcoma (n = 1). HRAS mutations identified in those tumors included G13R (n = 2) and G12S, G12C, and Q61L (n = 1 each). Treatment was associated with grade 1/2 adverse events (AE) consistent with those expected from prior studies. Grade 3 or higher AEs on treatment were disease progression, dyspnea, and pleural effusion, not related to protocol therapy. One patient had stable disease (SD) at the end of cycle two and remained on protocol therapy for four cycles. There were no objective responses (OR). Conclusions This U.S. cooperative group study was successful at identifying pediatric patients with tumors that harbored oncogenic mutations in HRAS. The frequency of the mutations identified and patients enrolled was lower than anticipated and the study closed before accrual was complete. The adverse effect profile of tipifarnib in pediatric patients on the intermittent dosing schedule was acceptable. Limited single-agent efficacy of tipifarnib was observed in this biomarker-selected cohort of refractory pediatric tumors.
