AKT1 E17K activating hotspot specifically positioning capivasertib + fulvestrant in HR+/H...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-BREAST-AKT1-E17K-CAPIVASERTIB-CANDIDATE`
Type	Red flag
Status	reviewed 2026-04-29
Diseases	`DIS-BREAST`
Sources	`SRC-CAPITELLO291-TURNER-2023` `SRC-ESMO-BREAST-METASTATIC-2024` `SRC-NCCN-BREAST-2025`

Red Flag Origin

Definition	AKT1 E17K activating hotspot specifically positioning capivasertib + fulvestrant in HR+/HER2- metastatic breast post-endocrine ± CDK4/6i. CAPItello-291 (Turner 2023) enrolled patients with PIK3CA / AKT1 / PTEN-altered tumors; AKT1 E17K accounted for ~7% of the altered cohort. Capivasertib + fulvestrant mPFS 7.3 vs 3.1 mo (HR 0.50, p<0.001) in the altered population. AKT1 E17K is the dominant (>90%) AKT1 hotspot. Candidate RF specifically anchors the E17K → capivasertib pairing distinct from the broader RF-BREAST-AKT1-E17K-ACTIONABLE.
Clinical direction	intensify
Category	high-risk-biology

Trigger Logic

{
  "all_of": [
    {
      "finding": "akt1_e17k",
      "value": true
    }
  ],
  "any_of": [
    {
      "finding": "prior_endocrine_therapy",
      "value": true
    },
    {
      "finding": "prior_cdk46i_progression",
      "value": true
    }
  ],
  "type": "biomarker"
}

Notes

Pairs AKT1 E17K with prior-therapy class gate (post-endocrine ± CDK4/6i) — closer to actual CAPItello-291 enrollment criterion than the broader RF-BREAST-AKT1-E17K-ACTIONABLE (priority 65, fires on E17K alone). Priority 66 sits adjacent so engine resolution behavior is deterministic when both fire (same clinical_direction = intensify). Toxicity: diarrhea (~70%), rash (~35%), hyperglycemia (~16%) — class on-target effects; lower hyperglycemia rate vs alpelisib. Pre-treatment fasting glucose + HbA1c required; diabetes optimization plan. Concurrent PIK3CA + AKT1 + PTEN testing recommended at first AI ± CDK4/6i progression — any single alteration triggers pathway-targeted therapy. CAPItello-291 trial Source ingested (SRC-CAPITELLO291-TURNER- 2023).

Used By

Indications

IND-BREAST-HR-POS-2L-FUL-EVEROLIMUS - IND-BREAST-HR-POS-2L-FUL-EVEROLIMUS