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RB1-Loss Pan-Cancer Dependency Atlas - Phase 5: TCGA Clinical Integration
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Estimated total US RB1-loss cancer patients/year: ~125,127

RB1-LOSS PREVALENCE BY CANCER TYPE
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  Retinoblastoma: 100% loss, ~300 pts/yr
  SCLC: 95% loss, ~28,500 pts/yr
  SARC_osteo: 65% loss, ~2,340 pts/yr
  BLCA_neuro: 40% loss, ~640 pts/yr
  PRAD_NEPC: 40% loss, ~2,320 pts/yr
  BLCA: 18% loss, ~14,974 pts/yr
  BRCA_TNBC: 12% loss, ~5,592 pts/yr
  PRAD: 12% loss, ~34,596 pts/yr
  GBM: 10% loss, ~1,400 pts/yr
  OV_HGSC: 8% loss, ~1,096 pts/yr
  LUSC: 8% loss, ~4,702 pts/yr
  SARC: 8% loss, ~1,087 pts/yr
  UCEC: 6% loss, ~4,072 pts/yr
  LIHC: 6% loss, ~2,472 pts/yr
  LUAD: 5% loss, ~2,938 pts/yr
  ESCA: 5% loss, ~1,118 pts/yr
  PAAD: 5% loss, ~3,322 pts/yr
  STAD: 4% loss, ~1,075 pts/yr
  HNSC: 4% loss, ~2,338 pts/yr
  SKCM: 4% loss, ~4,025 pts/yr
  COADREAD: 3% loss, ~4,584 pts/yr
  KIRC: 2% loss, ~1,636 pts/yr

CDK2 INHIBITOR CLINICAL LANDSCAPE
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  INX-315 (Incyte, Phase 1/2): NCT05735080
    Biomarkers: CCNE1 amplification, RB1 loss
    Tumor types: Breast; Ovarian; Endometrial; Solid tumors
    Includes RB1 loss: YES
  PF-07220060 (Pfizer, Phase 1): NCT05757544
    Biomarkers: CCNE1 amplification, CDK4/6i-resistant
    Tumor types: Breast; Solid tumors
    Includes RB1 loss: NO

OTHER RELEVANT TRIALS FOR RB1-LOSS CANCERS
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  Alisertib (AURKA) (Phase 2): SCLC
    Activity in SCLC (RB1-loss enriched)
  Lurbinectedin (Approved): SCLC
    Approved for relapsed SCLC
  Tarlatamab (DLL3 BiTE) (Approved): SCLC
    DLL3-targeting bispecific, approved SCLC

PRIORITY RANKING (CDK2 SL strength x population x drug availability)
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  SKCM: score=25.6, CDK2 d=-1.545 [lineage-specific], ~4,025 pts/yr
  SARC_osteo: score=14.4, CDK2 d=-0.929 [lineage-specific], ~2,340 pts/yr
  BLCA: score=12.5, CDK2 d=-0.648 [lineage-specific], ~14,974 pts/yr
  KIRC: score=12.1, CDK2 d=0.821 [lineage-specific], ~1,636 pts/yr
  PRAD: score=10.9, CDK2 d=-0.524 [pan-cancer pooled], ~34,596 pts/yr
  UCEC: score=10.9, CDK2 d=-0.656 [lineage-specific], ~4,072 pts/yr
  PAAD: score=10.7, CDK2 d=-0.661 [lineage-specific], ~3,322 pts/yr
  OV_HGSC: score=10.4, CDK2 d=-0.746 [lineage-specific], ~1,096 pts/yr
  LIHC: score=9.1, CDK2 d=-0.580 [lineage-specific], ~2,472 pts/yr
  SCLC: score=8.7, CDK2 d=-0.425 [lineage-specific], ~28,500 pts/yr
  GBM: score=8.5, CDK2 d=-0.584 [lineage-specific], ~1,400 pts/yr
  BLCA_neuro: score=8.4, CDK2 d=-0.648 [lineage-specific], ~640 pts/yr
  PRAD_NEPC: score=8.1, CDK2 d=-0.524 [pan-cancer pooled], ~2,320 pts/yr
  LUSC: score=7.2, CDK2 d=-0.425 [lineage-specific], ~4,702 pts/yr
  LUAD: score=6.8, CDK2 d=-0.425 [lineage-specific], ~2,938 pts/yr

SCLC DEEP-DIVE
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  RB1 loss: ~95% (near-universal)
  TP53 co-loss: ~98% (hallmark of SCLC)
  5-year survival: <7%
  Standard of care: platinum + etoposide + IO
  Unmet need: Nearly all patients relapse
  CDK2 dependency (DepMap): ROBUST (d=-0.524 pan-cancer)
  Key opportunity: CDK2 inhibitors as targeted therapy for SCLC
  SCLC has no approved targeted therapies — CDK2i could be first-in-class

CO-ALTERATION LANDSCAPE
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  RB1+TP53 co-loss: Defines SCLC, common in NEPC and osteosarcoma
  RB1+CCNE1 amp: Intensifies CDK2 dependency (d=-2.236 in DepMap)
  RB1+MYC amp: Drives proliferation, may modify dependency landscape
  SCLC: RB1+TP53 = SCLC hallmark
  BRCA_TNBC: CCNE1 amp intensifies CDK2 dep
  OV_HGSC: CCNE1 amp intensifies CDK2 dep

CLINICAL RECOMMENDATIONS
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  1. SCLC: Highest priority for CDK2 inhibitor trials (~28,500 RB1-loss/yr)
  2. Prostate (NEPC): RB1 loss enriched in treatment-resistant disease
  3. Bladder: 18% RB1 loss, large population (~15,000 pts/yr)
  4. TNBC: RB1+CCNE1 co-alteration subgroup most CDK2-dependent
  5. Osteosarcoma: 65% RB1 loss, pediatric unmet need

Sources: TCGA PanCanAtlas, ACS 2024, ClinicalTrials.gov, ASCO 2025
