Predictive and prognostic molecular biomarkers in lymphomas.

Recent advances in molecular diagnostics have markedly expanded our understanding of the genetic underpinnings of lymphomas and catalysed a transformation in not just how we classify lymphomas, but also how we treat, target, and monitor affected patients. Reflecting these advances, the World Health Organization Classification, International Consensus Classification, and National Comprehensive Cancer Network guidelines were recently updated to better integrate these molecular insights into clinical practice. We summarise here the molecular biomarkers of lymphomas with an emphasis on biomarkers that have well-supported prognostic and predictive utility, as well as emerging biomarkers that show promise for clinical practice. These biomarkers include: (1) diagnostic entity-defining genetic abnormalities [e.g., B-cell acute lymphoblastic leukaemia (B-ALL) with KMT2A rearrangement]; (2) molecular alterations that guide patients' prognoses (e.g., TP53 loss frequently conferring worse prognosis); (3) mutations that serve as the targets of, and often a source of acquired resistance to, small molecular inhibitors (e.g., ABL1 tyrosine kinase inhibitors for B-ALL BCR::ABL1, hindered by ABL1 kinase domain resistance mutations); (4) the growing incorporation of molecular measurable residual disease (MRD) in the management of lymphoma patients (e.g., molecular complete response and sequencing MRD-negative criteria in multiple myeloma). Altogether, our review spans the spectrum of lymphoma types, from the genetically defined subclasses of precursor B-cell lymphomas to the highly heterogeneous categories of small and large cell mature B-cell lymphomas, Hodgkin lymphomas, plasma cell neoplasms, and T/NK-cell lymphomas, and provides an expansive summary of our current understanding of their molecular pathology.

Molecular marker testing and reporting completeness for adult-type diffuse gliomas in the United States.

Background: A newly developed brain molecular marker (BMM) data item was implemented by US cancer registries for individuals diagnosed with brain tumors in 2018-including IDH and 1p/19q-co-deletion statuses for adult-type diffuse gliomas. We thus investigated the testing/reporting completeness of BMM in the United States. Methods: Cases of histopathologically confirmed glioblastoma, astrocytoma, and oligodendroglioma diagnosed in 2018 were identified in the National Cancer Database. Adjusted odds ratios (ORadj) and 95% confidence intervals (CI) of BMM testing/reporting were evaluated for association with the selected patient, treatment, and facility-level characteristics using multivariable logistic regression. As a secondary analysis, predictors of MGMT promoter methylation testing/reporting among IDH-wildtype glioblastoma individuals were assessed. Key limitations of the BMM data item were that it did not include any details regarding testing technique or assay type and could not distinguish between a lack of testing and a lack of cancer registry reporting of testing results. Results: Among 8306 histopathologically diagnosed adult-type diffuse gliomas nationally, overall BMM testing/reporting completeness was 81.1%. Compared to biopsy-only cases, odds of testing/reporting increased for subtotal (ORadj= 1.38 [95% CI: 1.20-1.59], P < .001) and gross total resection (ORadj=1.50 [95% CI: 1.31-1.72], P < .001). Furthermore, the odds were lowest at community centers (hospitals (67.3%; ORadj=0.35 [95% CI: 0.26-0.46], P < .001) and highest at academic/NCI-designated comprehensive cancer centers (85.4%; referent). By geographical location, BMM testing/reporting completeness ranged from a high of 86.8% at New England (referent) to a low of 76.0 % in the West South Central region (ORadj=0.57 [95% CI: 0.42-0.78]; P < .001). Extent of resection, Commission-on-Cancer facility type, and facility location were additionally significant predictors of MGMT testing/reporting among IDH-wildtype glioblastoma cases. Conclusions: Initial BMM testing/reporting completeness for individuals with adult-type diffuse gliomas in the United States was promising, although patterns varied by hospital attributes and extent of resection.

Use of First-Line Immune Checkpoint Inhibitors and Association With Overall Survival Among Patients With Metastatic Melanoma in the Anti-PD-1 Era.

Importance: In 2015, first-line programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) were Food and Drug Administration (FDA)-approved and National Comprehensive Cancer Network (NCCN)-recommended for patients with stage IV melanoma. Few studies have assessed the overall survival (OS) and usage rate associated with first-line ICI following 2015. Objective: To determine the rates of ICI use for metastatic melanoma following FDA approval in 2015 and characterize OS associated with first-line ICI use in this patient population. Design, Setting, and Participants: In this retrospective, nationwide cohort study, adult patients (≥20 years of age) with newly diagnosed stage IV cutaneous melanoma from 2010 to 2019 were identified using the US National Cancer Database (NCDB). Data were released by NCDB in March 2022 and analyzed in June 2022. Interventions: Patients were compared based on first-line ICI receipt vs not. Main Outcomes and Measures: The OS and use of first-line ICI in 2016 to 2019 were assessed using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, landmark time points were used (the 50th and 75th percentile times from diagnosis to ICI initiation). Results: Among 16 831 patients with stage IV melanoma, 11 435 (67.9%) of patients were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15 711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; the median (IQR) age at diagnosis was 64 (54-73) years. First-line immunotherapy use increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and 62.5% (1223 of 1958) in 2019. Median OS improved from 7.7 months (95% CI, 7.1-8.6 months) in 2010 to 17.5 months (95% CI, 14.9-19.8 months) in 2018. For patients diagnosed in 2016 or later, OS improved with first-line ICI (median OS using the 78-day landmark: 43.7 months [95% CI, 38.1-49.1 months] vs 16.1 months [95% CI, 13.5-19.3 months] for targeted therapy or chemotherapy; adjusted P < .001)-even after adjusting for patient, disease, and treatment factors. Results were similar for the 48-day landmark. This included patients presenting with brain metastases (first-line ICI median OS using the 78-day landmark: 19.9 months [95% CI, 17.2-25.0 months] vs 10.7 months for targeted therapy [95% CI, 9.5-12.3 months], adjusted P = .001). First-line ICI use varied by patients' age, insurance status, zip code-level household income, and treating hospital type. Conclusions and Relevance: Following anti-PD-1 approval in 2015, first-line ICI was associated with substantial OS improvements for patients with stage IV melanoma, including those with brain metastases. As of 2019, 38% of patients still were not receiving first-line ICI in the US, with use varying by patients' socioeconomic factors.

Underutilization of Guideline-Recommended Mismatch Repair/Microsatellite Instability Biomarker Testing in Advanced Colorectal Cancer.

BACKGROUND: In 2017, DNA mismatch repair/microsatellite instability (MMR/MSI) testing was nationally recommended for advanced colorectal cancers based on favorable immune checkpoint inhibitor responses among patients with MMR-deficient/MSI-high tumors. METHODS: Patients ages ≥20-years-old presenting with stage IV colorectal adenocarcinoma from 2010 to 2017 were identified from the National Cancer Database. 2017 was the latest year with available testing utilization data. Patient, tumor, socioeconomic, and care setting characteristics were evaluated for association with upfront MMR/MSI testing in 2017 using multivariable logistic regression and average adjusted predicted probabilities (%AAP). RESULTS: Among 72,830 stage IV colorectal cancers, upfront MMR/MSI testing levels increased from 16.4% in 2010 to 56.4% in 2017. For patients diagnosed in 2017 (i.e., following national recommendations, n = 10,022), testing levels were lower for older patients (Padj < 0.001), and were independent of patients' race/ethnicity and insurance status. Patients from the poorest quartile of households received less testing [49.6%AAP, 99.9% confidence interval (CI) 45.5-53.7] than patients from the 3rd (56.9%AAP, 99.9% CI, 53.3-60.6; Padj < 0.001) or 4th quartiles (57.6%AAP, 99.9% CI, 54.3-60.9; Padj < 0.001). Although testing levels improved most at community programs, they remained lower in 2017 (46.6%AAP, 99.9% CI, 41.0-52.1) compared with academic/NCI-designated comprehensive cancer centers (62.8%AAP, 99.9% CI, 59.7-65.8; Padj < 0.001). CONCLUSIONS: Upfront MMR/MSI testing utilization for patients with advanced colorectal cancer has increased but there is still substantial need for optimization. Testing utilization disproportionately lagged for patients who were older, from the poorest quartile of households, or managed at community cancer programs. IMPACT: Our findings indicate opportunities for improving rates of MMR/MSI testing and reporting, possibly through incorporation into quality control and accreditation metrics.