Maria Hafez, Assistant Professor at St. Luke’s University Health Network, shared on LinkedIn:
“Day 3 at ESMO26: Komal Jhaveri, gave a ‘Moneyball’ view of adjuvant ER+ therapy. We are moving from treating by appearance (stage, nodes, grade) to treating by biology, measured over time.
The unmet need: 20–40% of patients with ER+ early breast cancer have a distant recurrence despite endocrine therapy, and about half stop ET before 5 years, mostly because of side effects.
Her three levers:
CDK4/6 inhibitors
- monarchE (7 years): iDFS HR 0.73, Δ6.5%, with an established OS benefit. The benefit was seen regardless of inferred Oncotype score.
- NATALEE (6 years): iDFS HR 0.74 (Δ5.3%), with an OS trend (HR 0.81).
- Benefit held in patients ≤40. No biomarker yet identifies who will not benefit.
- About 20% stop early because of toxicity. Dose reductions did not reduce efficacy, and step-up abemaciclib dosing (TRADE) kept 70.8% of patients at target dose by week 12, compared with ~60% in monarchE.
A better endocrine backbone: oral SERDs
- lidERA is the first positive adjuvant oral SERD trial: giredestrant vs standard ET, iDFS HR 0.70, with fewer arthralgia-related discontinuations. It also enrolled patients CDK4/6i trials did not, such as higher-risk stage I disease.
- Her proposed framework, if giredestrant is approved: when CDK4/6i is not an option (access, toxicity, patient preference), strongly consider giredestrant. For stage II–III, a SERD after CDK4/6i may be the future. That depends on sequential trials (CAMBRIA-1, EMBER-4, ELEGANT; readouts from 2027).
- Open questions: there was no CDK4/6i in lidERA, the readout is early, few tumours had ESR1 mutations, treatment of premenopausal patients varied, and cost is unknown.
Personalize over time with ctDNA/MRD
- Her Formula 1 analogy: the telemetry works, but does an early pit stop win the race?
- In a monarchE ctDNA subset (enriched for events), 4-year iDFS was 87.5% with persistently negative ctDNA. Among patients whose ctDNA turned positive, 93% had an IDFS event.
- AFT-70 NAVIGATE, which she co-chairs, randomizes ctDNA-negative patients (~2,572) to AI/tamoxifen + CDK4/6i or giredestrant alone, adding CDK4/6i only if ctDNA turns positive. The primary endpoint is 4-year DRFS (non-inferiority).
Clinical takeaway
We are moving from “one size fits many” to the right therapy at the right time for the right patient. Adjuvant CDK4/6i benefit is durable, so managing toxicity early is as important as choosing the drug. Oral SERDs are coming, and ctDNA may soon tell us who needs more and who can safely have less.”
You can also read: ESMO 2026: 10 Breast Cancer ADCs to Watch in Madrid
