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gh-k-dense-ai-claude-scient…/skills/clinical-decision-support/assets/example_gbm_cohort.md
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Example: GBM Molecular Subtype Cohort Analysis

Clinical Context

This example demonstrates a patient cohort analysis stratified by molecular biomarkers, similar to the GBM Mesenchymal-Immune-Active cluster analysis provided as reference.

Cohort Overview

Disease: Glioblastoma (GBM), IDH-wild-type

Study Population: n=60 patients with newly diagnosed GBM treated with standard Stupp protocol (temozolomide + radiation → adjuvant temozolomide)

Molecular Classification: Verhaak 2010 subtypes with immune signature refinement

  • Group A: Mesenchymal-Immune-Active subtype (n=18, 30%)
  • Group B: Other molecular subtypes (Proneural, Classical, Neural) (n=42, 70%)

Study Period: January 2019 - December 2022

Data Source: Single academic medical center, retrospective cohort analysis

Biomarker Classification

Mesenchymal-Immune-Active Subtype Characteristics

Molecular Features:

  • NF1 alterations (mutations or deletions): 72% (13/18)
  • High YKL-40 (CHI3L1) expression: 100% (18/18, median z-score +2.8)
  • Immune gene signature: Elevated (median ESTIMATE immune score +1250)
  • CD163+ macrophage infiltration: High density (median 195 cells/mm², range 120-340)
  • MES (mesenchymal) signature score: >0.5 (all patients)

Clinical Characteristics:

  • Median age: 64 years (range 42-76)
  • Male: 61% (11/18)
  • Tumor location: Temporal lobe predominant (55%)
  • Multifocal disease: 33% (6/18) - higher than overall cohort

Comparison Groups (Other Subtypes)

Molecular Features:

  • Proneural: n=15 (25%) - PDGFRA amplification, younger age
  • Classical: n=18 (30%) - EGFR amplification, chromosome 7+/10-
  • Neural: n=9 (15%) - neuronal markers, may include normal tissue

Treatment Outcomes

Response Assessment (RANO Criteria)

Objective Response Rate (after chemoradiation, ~3 months):

  • Mesenchymal-Immune-Active: 6/18 (33%) - CR 0, PR 6
  • Other subtypes: 18/42 (43%) - CR 1, PR 17
  • p = 0.48 (Fisher's exact)

Interpretation: No significant difference in initial response rates

Survival Outcomes

Progression-Free Survival (PFS):

  • Mesenchymal-Immune-Active: Median 7.2 months (95% CI 5.8-9.1)
  • Other subtypes: Median 9.5 months (95% CI 8.1-11.3)
  • Hazard Ratio: 1.58 (95% CI 0.89-2.81), p = 0.12
  • 6-month PFS rate: 61% vs 74%

Overall Survival (OS):

  • Mesenchymal-Immune-Active: Median 12.8 months (95% CI 10.2-15.4)
  • Other subtypes: Median 16.3 months (95% CI 14.7-18.9)
  • Hazard Ratio: 1.72 (95% CI 0.95-3.11), p = 0.073
  • 12-month OS rate: 55% vs 68%
  • 24-month OS rate: 17% vs 31%

Interpretation: Trend toward worse survival in mesenchymal-immune-active subtype, not reaching statistical significance in this cohort size

Response to Bevacizumab at Recurrence

Subset Analysis (patients receiving bevacizumab at first recurrence, n=35):

  • Mesenchymal-Immune-Active: n=12
    • ORR: 58% (7/12)
    • Median PFS2 (from bevacizumab start): 6.8 months
  • Other subtypes: n=23
    • ORR: 35% (8/23)
    • Median PFS2: 4.2 months
  • p = 0.19 (Fisher's exact for ORR)
  • HR for PFS2: 0.62 (95% CI 0.29-1.32), p = 0.21

Interpretation: Exploratory finding suggesting enhanced benefit from bevacizumab in mesenchymal-immune-active subtype (not statistically significant with small sample)

Safety Profile

Treatment-Related Adverse Events (Temozolomide):

No significant differences in toxicity between molecular subtypes:

  • Lymphopenia (any grade): 89% vs 86%, p = 0.77
  • Thrombocytopenia (grade 3-4): 22% vs 19%, p = 0.79
  • Fatigue (any grade): 94% vs 90%, p = 0.60
  • Treatment discontinuation: 17% vs 14%, p = 0.77

Clinical Implications

Treatment Recommendations

For Mesenchymal-Immune-Active GBM:

  1. First-Line: Standard Stupp protocol (no change based on subtype)

    • Evidence: No proven benefit for alternative first-line strategies
    • GRADE: 1A (strong recommendation, high-quality evidence)

  2. At Recurrence - Consider Bevacizumab Earlier:

    • Rationale: Exploratory data suggesting enhanced anti-angiogenic response
    • Evidence: Mesenchymal GBM has high VEGF expression, angiogenic phenotype
    • GRADE: 2C (conditional recommendation, low-quality evidence from subset)

  3. Clinical Trial Enrollment - Immunotherapy Combinations:

    • Rationale: High immune cell infiltration may predict immunotherapy benefit
    • Targets: PD-1/PD-L1 blockade ± anti-CTLA-4 or anti-angiogenic agents
    • Evidence: Ongoing trials (CheckMate-498, CheckMate-548 showed negative results, but did not select for immune-active)
    • GRADE: R (research recommendation)

For Other GBM Subtypes:

  • Standard treatment per NCCN guidelines
  • Consider tumor treating fields (Optune) after radiation completion
  • Clinical trials based on specific molecular features (EGFR amplification → EGFR inhibitor trials)

Prognostic Information

Counseling Patients:

  • Mesenchymal-immune-active subtype associated with trend toward shorter survival (12.8 vs 16.3 months)
  • Not definitive due to small sample size and confidence intervals overlapping
  • Prospective validation needed
  • Should not alter standard first-line treatment

Study Limitations

  1. Small Sample Size: n=18 in mesenchymal-immune-active group limits statistical power
  2. Retrospective Design: Potential selection bias, unmeasured confounders
  3. Single Institution: May not generalize to other populations
  4. Heterogeneous Recurrence Treatment: Not all patients received bevacizumab; treatment selection bias
  5. Molecular Classification: Based on bulk tumor RNA-seq; intratumoral heterogeneity not captured
  6. No Central Pathology Review: Molecular classification performed locally

Future Directions

  1. Prospective Validation: Confirm survival differences in independent cohort (n>100 per group for adequate power)
  2. Biomarker Testing: Develop clinically feasible assay for mesenchymal-immune subtype identification
  3. Clinical Trial Design: Immunotherapy combinations targeting mesenchymal-immune-active GBM specifically
  4. Mechanistic Studies: Investigate why mesenchymal-immune GBM may respond better to bevacizumab
  5. Longitudinal Analysis: Track molecular subtype evolution over treatment course

Data Presentation Example

Baseline Characteristics Table

Characteristic                    Mesenchymal-IA (n=18)  Other (n=42)  p-value
Age, years (median [IQR])         64 [56-71]            61 [53-68]    0.42
Sex, n (%)
  Male                            11 (61%)              24 (57%)      0.78
  Female                          7 (39%)               18 (43%)
ECOG PS, n (%)
  0-1                             15 (83%)              37 (88%)      0.63
  2                               3 (17%)               5 (12%)
Tumor location
  Frontal                         4 (22%)               15 (36%)      0.35
  Temporal                        10 (56%)              16 (38%)
  Parietal/Occipital              4 (22%)               11 (26%)
Extent of resection
  Gross total                     8 (44%)               22 (52%)      0.58
  Subtotal                        10 (56%)              20 (48%)
MGMT promoter methylated          5 (28%)               18 (43%)      0.27

Survival Outcomes Summary

Endpoint                          Mesenchymal-IA        Other         HR (95% CI)        p-value
Median PFS, months (95% CI)       7.2 (5.8-9.1)        9.5 (8.1-11.3) 1.58 (0.89-2.81)   0.12
6-month PFS rate                  61%                  74%
Median OS, months (95% CI)        12.8 (10.2-15.4)     16.3 (14.7-18.9) 1.72 (0.95-3.11) 0.073
12-month OS rate                  55%                  68%
24-month OS rate                  17%                  31%

Key Takeaways

  1. Molecular heterogeneity exists in GBM with distinct subtypes
  2. Mesenchymal-immune-active subtype characterized by NF1 alterations, immune infiltration
  3. Trend toward worse prognosis but not statistically significant (power limitations)
  4. Potential bevacizumab benefit hypothesis-generating, requires prospective validation
  5. Immunotherapy target: High immune infiltration rational for checkpoint inhibitor trials
  6. Clinical implementation pending: Need prospective validation before routine subtyping

References

  1. Verhaak RG, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110.
  2. Wang Q, et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32(1):42-56.
  3. Stupp R, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. NEJM. 2005;352(10):987-996.
  4. Gilbert MR, et al. Bevacizumab for Newly Diagnosed Glioblastoma. NEJM. 2014;370(8):699-708.
  5. NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2024.

This example demonstrates:

  • Biomarker-based stratification methodology
  • Outcome reporting with appropriate statistics
  • Clinical contextualization of findings
  • Evidence-based recommendations with grading
  • Transparent limitation discussion
  • Structure suitable for pharmaceutical/clinical research documentation
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