Test-directed chemo de-escalation in clinically high-risk HR+/HER2- early breast cancer with 0-9 involved nodes - UK NIHR / UCL / Warwick CTU
Discover KOL Sentiment on OPTIMA →Design - Phase 3 Prosigna PAM50 (ROR) test-directed chemotherapy de-escalation vs chemotherapy-for-all, clinically high-risk HR+/HER2- early breast cancer with 0-9 involved nodes, age 40 or older (ISRCTN42400492; 4,429 patients randomized 1:1 before testing); co-primary outcomes per the trial registry and protocol: invasive breast cancer-free survival in the per-protocol population (non-inferiority, 3% absolute margin at 5 years) and cost-effectiveness versus standard practice. This page covers the UK-led OPTIMA breast cancer trial; other studies also use the OPTIMA name.
Primary result (on-page result-block) - Non-inferiority met - 5-yr invasive breast cancer-free survival 91.8% (control) vs 90.3% (test-directed), HR 1.03 (90% CI 0.85-1.25); per-protocol population; p=0.006 for the pre-specified 3% non-inferiority margin (ASCO 2026 presented slide). ASCO 2026 Abstract 500 text: 91.5% vs 90.4%, HR 0.99 (90% CI 0.81-1.20), non-inferiority p=0.013 (median follow-up 3.9 years).
Clinical reach - In the test-directed arm, 68% of per-protocol patients (1,421 of 2,094) had a Prosigna ROR of 60 or below and received endocrine therapy alone, without chemotherapy.
Economics (ESMO 2026, LBA86) - Cost-effectiveness is a co-primary outcome per the trial registry and protocol. In the prespecified 2-year within-trial economic evaluation (UK NHS perspective, n=3,425), test-directed treatment cost £654 less per patient (95% CI −£1,525 to £218) and gave 0.05 more QALYs (0.02 to 0.08) than chemotherapy for all; 32% of the test-directed arm received chemotherapy. The investigators conclude that test-directed chemotherapy dominated standard care over 2 years; a lifetime model is in progress. (ESMO 2026 abstract LBA86; Hall, ESMO 2026, October 25, 2026)
Open questions - The investigators concluded the test can assist chemotherapy decisions in patients with 4-9 involved nodes or stage IIIA tumors; KOLs including Piccart and Sammons noted the relatively small key subpopulations and short follow-up (median 4 years).
Regulatory - Investigational strategy trial - not a drug approval; Prosigna is an FDA-cleared test (Veracyte).
Sponsor - UK NIHR / UCL / Warwick Clinical Trials Unit; Prosigna PAM50 assay (Veracyte).
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated October 26, 2026 (ESMO 2026 economic analysis, slides and physician reactions).
Precision medicine not only benefit patients, but also systems! @breastDoktor https://t.co/6SMQTkwgY6
Co-primary endpoint of OPTIMA-health economics (#ESMO26 LBA86): test-directed treatment cut chemo costs by £3,611/pt. After the £1,955 assay: net −£654/pt, +0.05 QALYs. Much better for patients, not more expensive for the NHS #bcsm https://t.co/vvSVZvMxiK
Latest KOL reactions surfaced first, then top tweets by impressions — click to view on X
#OPTIMA addresses a real and long-standing tension in how we treat premenopausal node-positive ER+ breast cancer. The signal is meaningful: PAM50 ROR<60 patients who received adequate OFS did not appear to benefit from chemotherapy. That is a hypothesis worth taking seriously.
Such important information answering an important question. Question I have is how these results will guide our choice of genomic assay going forward in this patient population.
🚨 The OncoAlert #BreastCancer faculty’s TOP 10 abstracts for #ASCO26 — selected by our leads and finalized through a Delphi voting process with senior breast cancer experts. 1️⃣ 500 — OPTIMA Test-directed chemotherapy in high-risk ER+/HER2- early BC 2️⃣ LBA1006 — PERSEVERA BC https://t.co/FJSHDjv3Ln
#ASCO26 | We've been sparing node-negative #breastcancer patients from chemo using #Oncotype. #OPTIMA just did it in the population we've been most afraid to touch. 4,400+ patients. ER+/HER2−. Node-positive, up to pN2. #Prosigna_ROR: ≤60 → no chemo. 5-year IBCFS: 90.4% vs
💫🌟🚨 Top 10 #BreastCancer abstracts for #ASCO26 — selected by our leads and finalized via a Delphi voting process 🗳️🔬 1️⃣ 500 — OPTIMA 2️⃣ LBA1006 — PERSEVERA BC 3️⃣ 507 — KEYNOTE-522 final analysis 4️⃣ LBA1007 — SERENA-6 5️⃣ 502 — LIDERA BC 6️⃣ LBA1000 — ASCENT-04 7️⃣ 501 — NATALEE https://t.co/3BPHgMO1ct
#ASCO26 Can genomic testing safely spare chemotherapy in high-risk ER+/HER2- early breast cancer? The phase III OPTIMA trial says yes. 🧬 4,429 pts 🧪 Prosigna (PAM50)-guided strategy 🎯 Majority node-positive disease Key finding: Low-risk ROR (≤60) patients had excellent https://t.co/22ZadcSpgb https://t.co/cL8NHWlJqh
🧬 OPTIMA is a major de-escalation signal in mostly node-positive HR+/HER2− early breast cancer. In >4,400 pts, Prosigna/PAM50-guided chemotherapy decisions met non-inferiority vs standard chemo for 5-year IBCFS: 90.4% vs 91.5%, HR 0.99. This included premenopausal pts on OFS
First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer. #ASCO26 Abstract Preview https://t.co/vm2tCjbnd8 The OPTIMA trial evaluated Prosigna https://t.co/tLC2NO2dw9
#asco26. Stein presents data from optima. Using Prosigna to determine chemo benefit in early HR+ BC. Premenopausal women <40 where we stillneed info excluded. Shows Prosigna identifies N+ pts unlikely to benefit from chemo. IMP! 1500 older premen pts included. @OncoAlert https://t.co/MeAaes5bL9
Dr Piccart reinforces that OPTIMA for the first time prospectively shows the chemo benefit for premenopausal low GEP women, is mostly due to chemotherapy induced ovarian suppression. https://t.co/QNSOtlyjqm
#ASCO26 OPTIMA does not teach us a completely new biology; it reinforces the Oncotype DX-era message with Prosigna/PAM50 at a phase III level. What makes it important is the population: clinically high-risk ER+/HER2− EBC, frequent nodal positivity, 19% pN2 disease, and 37% https://t.co/qaIrXJTs0P
How will OPTIMA change our practice ? #ASCO26 @OncoAlert @ASCO https://t.co/c0yCb5l39T https://t.co/vzmDSkv0ZO
OPTIMA Trial #ASCO26 The 50-gene Prosigna test identifies ~2/3 of ER+/HER2− early breast cancer patients — including those with node-positive disease & premenopausal women ≥40 — who derive no meaningful benefit from adjuvant chemotherapy. 5-yr IBCFS: 90.3% vs 91.8% → https://t.co/8TRrnqdsBK
OPTIMA asks a long-standing clinical de-escalation question: can biology-guided genomic testing safely spare adjuvant chemotherapy in women and men aged 40 or older with clinically high-risk ER+/HER2- early breast cancer — a population where adjuvant chemo has historically been the default? Earlier de-escalation trials (TAILORx, RxPONDER) addressed node-negative and limited node-positive disease using Oncotype DX. OPTIMA extends the question into a higher-risk, more chemotherapy-committed population (up to nine involved nodes, including pN2) and uses a different assay — the 50-gene Prosigna PAM50 ROR (Risk of Recurrence) test — to identify a low-risk biology subgroup that may not benefit from chemotherapy.
The trial is a UK NIHR-funded, investigator-led Phase III non-inferiority study coordinated by the Warwick Clinical Trials Unit and University College London, with Robert Stein (UCL) presenting first results in an oral abstract session at ASCO 2026 (Abstract 500) on May 30, 2026. A total of 4,429 patients at sites in the UK, Norway, Sweden, Australia, New Zealand and Thailand were randomized 1:1 to chemotherapy followed by endocrine therapy for all (control) or to Prosigna test-directed treatment, in which patients with an ROR score above 60 received chemotherapy followed by endocrine therapy and those with an ROR score of 60 or below received endocrine therapy alone. Premenopausal women received ovarian function suppression. The primary question is whether the test-directed (chemo-sparing) strategy is non-inferior to standard-of-care chemo-plus-endocrine therapy at 5 years.
The result is being discussed by KOLs as a potential practice-changing chemo de-escalation signal for a much larger, higher-risk population than previous genomic tests have validated — while also drawing nuanced commentary from Martine Piccart, Dr Sarah Sammons, Yakup Ergün and others on subgroup limits (particularly N2 disease, where event counts remain low) and on the practical question of how widely the strategy will be adopted given existing competing assays.
UK NIHR-funded, investigator-led, multicenter Phase III randomized non-inferiority trial (ISRCTN42400492). Coordinated by Warwick Clinical Trials Unit and UCL. All eligible patients were randomized 1:1 to standard care (adjuvant chemotherapy followed by endocrine therapy for all) or test-directed treatment (Prosigna test on the primary tumor: ROR above 60, chemotherapy followed by endocrine therapy; ROR 60 or below, endocrine therapy alone). Control-arm tumors were tested blinded, for analysis only. Premenopausal women received ovarian function suppression.
Clinically high-risk, ER+/HER2- early breast cancer, age ≥40, 0-9 involved axillary nodes, with a minimum tumor-size requirement for node-negative or micrometastatic disease. Women and men were eligible; premenopausal women received ovarian function suppression. 4,429 patients were randomized at sites in the UK, Norway, Sweden, Australia, New Zealand and Thailand (per-protocol population 4,153: 8% node-negative or micrometastatic, 73% 1-3 nodes, 19% 4-9 nodes). Notably, this is a substantially higher-risk and more node-positive population than TAILORx or RxPONDER.
Prosigna 50-gene PAM50 Risk of Recurrence (ROR) signature (Veracyte). Test performed on the primary tumor. Low-risk threshold pre-specified as ROR ≤60. Per the trial slides, 68% of the test-directed arm (1,421 of 2,094 per-protocol patients) had an ROR of 60 or below and received endocrine therapy alone.
Per the trial registry and protocol, the main trial has two primary outcomes: (1) invasive breast cancer-free survival (IBCFS) in the per-protocol population, tested for non-inferiority (margin: no more than a 3% absolute difference at 5 years; 90% confidence intervals), and (2) the cost-effectiveness of test-directed treatment versus standard clinical practice (prespecified 2-year within-trial analysis reported at ESMO 2026, LBA86; lifetime model-based analysis in progress). Key secondary endpoint: non-inferiority of IBCFS in the ROR 60-or-below subpopulation (3.5% margin). Other secondary outcomes include invasive disease-free survival, recurrence-free interval, distant recurrence-free interval, breast cancer-specific and overall survival, and quality of life. (ISRCTN registry; protocol v11.1, March 11, 2026)
ASCO 2026 presented slide. The 5-year IBCFS (invasive breast cancer-free survival) from the Kaplan-Meier curves (148 control vs 153 test-directed events) was 91.8% control vs 90.3% test-directed, hazard ratio 1.03 (90% CI 0.85-1.25, p=0.006 non-inferiority) — meeting the pre-specified 3% non-inferiority margin. In the key secondary ROR ≤60 subpopulation (patients from both arms; control-arm tumors tested blinded), 5-year IBCFS was 94.8% control vs 93.6% test-directed, HR 1.06 (90% CI 0.80-1.40; p=0.003 for 3.5% non-inferiority) (68 vs 76 events). Source: Kaplan-Meier slide presented by Robert C. Stein at ASCO 2026 (oral, Abstract 500), shared on X by KOLs; KOL posts from the presentation report a median follow-up of 4 years. On that slide, the observed 5-year differences favored chemotherapy by 1.5% overall and 1.2% in the ROR 60-or-below subpopulation; the investigators concluded that the test identifies a group with minimal if any chemotherapy benefit (at most 2 recurrences prevented per 100 patients).
ASCO 2026 Abstract 500 text. The published abstract reports slightly different figures: 5-year IBCFS 91.5% control vs 90.4% test-directed, HR 0.99 (90% CI 0.81-1.20), non-inferiority p=0.013 (280 events; median follow-up 3.9 years). In the ROR ≤60 population, 5-year IBCFS was 94.9% vs 93.7%, HR 1.06 (90% CI 0.78-1.46), non-inferiority p=0.0051. Neither source explains the difference between the two sets of figures. (J Clin Oncol 2026;44(16_suppl):500)
According to the trial slides shared by multiple KOLs (Nozawa, Griguolo, Lucarecco), the Prosigna ROR-low result identified roughly two-thirds (68%; 1,421 of 2,094 per-protocol patients in the test-directed arm) as ROR 60 or below, and these patients received endocrine therapy alone — meaning a majority of this previously "obligate-chemo" population could potentially be spared adjuvant chemotherapy under a test-directed strategy. This is the headline that KOLs are pointing to as the practice-changing element of OPTIMA: not the absolute survival numbers, but the size of the population the trial reclassifies.
Multiple KOLs (Dr Sarah Sammons, Martine Piccart in the discussion, Yakup Ergün) flagged the still-low event count in the pN2 (4-9 nodes) subgroup as the principal interpretive caveat — the headline non-inferiority result is most robust in the 1-3-node population. In her invited discussion, Piccart noted that some uncertainty remains given relatively small key subpopulations and short follow-up.
Source: Stein et al., ASCO 2026 oral presentation (Abstract #500), May 30 2026; OPTIMA trial slides shared on X by Rugo, Nozawa, Griguolo, Lucarecco, Y. Abdou, To Be Elizabeth.Cost-effectiveness is one of the main trial's two primary outcomes in the trial registry and protocol, alongside invasive breast cancer-free survival. The protocol plans two economic analyses: a within-trial analysis and a lifetime model-based analysis, which it names the method of choice for the primary economic outcome measure (cost per QALY). The LBA86 abstract describes the 2-year results as the “prespecified within-trial economic evaluation” and states that a lifetime decision model is in progress. (ISRCTN registry; protocol v11.1, sections 7 and 16.1)
Peter S. Hall (University of Edinburgh) presented the prespecified within-trial economic evaluation of OPTIMA in the Policy proffered paper session at ESMO 2026 (Madrid, October 25, 2026; invited discussant Winette T. van der Graaf). Costs and quality-adjusted life-years (QALYs, EQ-5D-3L) were measured over 2 years from the UK NHS perspective in 3,425 UK per-protocol participants (1,697 control, 1,728 test-directed). In the test-directed arm, patients received chemotherapy only if the Prosigna Risk of Recurrence score was above 60; 32% of that arm received chemotherapy, compared with all patients in the control arm.
Results. Mean 2-year costs were £16,460 with test-directed treatment and £17,111 with chemotherapy for all: an adjusted difference of −£654 per patient (95% CI −£1,525 to £218). Mean QALYs were 1.47 vs 1.42, an adjusted difference of 0.05 (0.02 to 0.08) (0.049 on the presented conclusions slide). Incremental net health benefit was 0.08 QALYs (0.03 to 0.13) at £20,000 per QALY and 0.07 (0.03 to 0.11) at £30,000, with a 100% probability of cost-effectiveness at both thresholds. The cost difference itself has a confidence interval that crosses zero; the saving came mainly from lower chemotherapy costs (−£3,611 per patient), partly offset by the assay, higher ovarian suppression costs and a numerically higher abemaciclib cost (confidence interval crosses zero) in the test-directed arm.
| Mean adjusted 2-year cost per patient (£) | Test-directed (n=1,728) | Control (n=1,697) | Difference (95% CI) |
|---|---|---|---|
| 50-gene assay (Prosigna) | 1,955 | 0 | +1,955 |
| Chemotherapy, total | 1,796 | 5,540 | −3,611 (−3,800 to −3,422) |
| Chemotherapy drugs | 39 | 124 | −82 (−91 to −73) |
| Chemotherapy delivery | 1,162 | 3,621 | −2,370 (−2,472 to −2,269) |
| Supportive medicines | 388 | 1,207 | −792 (−857 to −728) |
| Chemotherapy-related admissions | 207 | 588 | −367 (−483 to −250) |
| Radiotherapy | 4,066 | 3,954 | +137 (−6 to 279) |
| Abemaciclib | 5,823 | 5,275 | +382 (−446 to 1,210) |
| Ovarian suppression | 2,438 | 1,937 | +487 (470 to 504) |
| Endocrine therapy | 26 | 22 | +4 (3 to 6) |
| Post-randomization surgery | 11 | 15 | −3 (−21 to 16) |
| Breast imaging | 76 | 74 | +4 (2 to 7) |
| Other admissions | 266 | 292 | −9 (−109 to 91) |
| Total | 16,460 | 17,111 | −654 (−1,525 to 218) |
Conclusions as presented. The investigators conclude that test-directed chemotherapy dominated standard care over 2 years (lower costs and more QALYs) and, together with non-inferior invasive breast cancer-free survival, support adoption in the UK NHS, subject to confirmation in a lifetime decision model that is in progress. Per the conclusions slide, the test stays cost-saving up to a list price of about £2,550 and cost-effective up to £3,520 at £20,000 per QALY.
Test-directed: −£654 per patient · +0.05 QALYs · 2-year NHS analysisESMO 2026 abstract LBA86 · Hall, ESMO 2026 slides (photographed by Peter Dubsky; see Key Slides). Efficacy reference: Stein et al., ASCO 2026 Abstract #500.
OPTIMA is a UK-led international Phase 3 randomized trial (ISRCTN42400492; 4,429 patients) that tests whether a Prosigna PAM50 (Risk of Recurrence, ROR) test-directed strategy can safely de-escalate adjuvant chemotherapy in clinically high-risk HR-positive, HER2-negative early breast cancer with 0-9 involved lymph nodes. Patients randomized to the test-directed arm received chemotherapy only if their tumor was biologically high-risk. Per the trial registry and protocol, OPTIMA has two primary outcomes: invasive breast cancer-free survival, tested for non-inferiority, and the cost-effectiveness of test-directed treatment versus standard practice.
On the result slide presented at ASCO 2026 and shared by KOLs, the test-directed strategy met non-inferiority: 5-year invasive breast cancer-free survival was 91.8% in the control arm versus 90.3% in the test-directed arm (HR 1.03; 90% CI 0.85-1.25), within the pre-specified 3% non-inferiority margin. The ASCO 2026 Abstract 500 text reports 91.5% versus 90.4% (HR 0.99; 90% CI 0.81-1.20; median follow-up 3.9 years), also non-inferior.
OPTIMA is a biomarker-guided strategy trial, not a drug-approval study. It evaluates the Prosigna PAM50 (ROR) assay - an FDA-cleared, CE-marked test from Veracyte - as a tool to direct which clinically high-risk patients need adjuvant chemotherapy. No new drug is being tested or approved.
According to trial slides shared by multiple KOLs, the Prosigna test classified 68% of the test-directed arm (1,421 of 2,094 per-protocol patients) as ROR 60 or below; these patients received endocrine therapy alone. In the ROR 60-or-below subpopulation, 5-year invasive breast cancer-free survival was 93.6% without chemotherapy versus 94.8% with it (HR 1.06; 90% CI 0.80-1.40; non-inferior at a 3.5% margin), per the ASCO 2026 presented slide. The ASCO 2026 Abstract 500 text reports 93.7% versus 94.9% (HR 1.06; 90% CI 0.78-1.46).
The principal caveat, flagged by KOLs including Sarah Sammons and Martine Piccart, is the still-low event count in the pN2 (4-9 node) subgroup, where the non-inferiority conclusion is less robust. The headline result is most reliable in the 1-3-node population, and longer follow-up is needed before extending de-escalation to higher nodal burden.
Cost-effectiveness is one of OPTIMA's two primary outcomes per the trial registry and protocol. In the prespecified 2-year within-trial economic evaluation presented by Peter S. Hall at ESMO 2026 (LBA86, October 25, 2026), Prosigna test-directed treatment cost 654 pounds less per patient than chemotherapy for all (95% CI -1,525 to 218 pounds) and gave 0.05 more quality-adjusted life-years (0.02 to 0.08), from the UK NHS perspective in 3,425 per-protocol participants. Chemotherapy savings of 3,611 pounds per patient outweighed the 1,955-pound test cost. The investigators concluded that test-directed chemotherapy dominated standard care over 2 years; a lifetime decision model is in progress.
Primary publications, sponsor & institutional press releases, and major oncology media coverage around the Stein/UCL ASCO 2026 oral presentation.
“OPTIMA addresses a long-standing challenge in breast cancer care: identifying who truly benefits from chemotherapy and who does not. Our findings show that many patients can safely avoid chemotherapy without compromising their outcomes.”Source: EurekAlert / UCL · May 30 2026 ↗
“I will now recommend a genomic assay for all post- and premenopausal women (≥40 y) with any number of positive nodes. A low-risk genomic result triggers shared decision-making.”
All 31 curated OPTIMA-related tweets from #ASCO26 and pre-conference commentary, sorted positive → neutral → negative. Text is verbatim from each KOL.
On August 5, the Oncology Brothers asked how to adopt OPTIMA in practice. Seven physicians answered. The full exchange, verbatim and in order:
Still trying to figure out how to adopt the data from OPTIMA trial in my practice (and how to use OncotypeDx vs. PAM50 scoring/test). Who is the right patient? Should I pivot completely from other tests and just rely on PAM50? @ErikaHamilton9 @PTarantinoMD @hoperugo @DrSGraff
I feel most comfortable for postmenopausal node positive.
I would continue to use Oncotype as the default assay in standard node-negative disease and in postmenopausal patients with 1–3 positive nodes. In OPTIMA-eligible premenopausal patients aged ≥40 years who will receive optimal ovarian suppression, and in selected patients with 4–9 positive nodes, I would prefer Prosigna as the de-escalation assay. However, in an otherwise eligible patient whose chemotherapy I de-escalate, I would not yet omit an adjuvant CDK4/6 inhibitor.
Only thing I’d say about this is the 4-9 node group was a small minority of folks in the trial. I’m not ready to use it in this group but 1-3 nodes I think I’ll start moving in that direction.
I do not think the number of N2 patients is that low (20%). What concerns me more is that the follow-up remains too short for HR-positive breast cancer.
True, agree shorter term follow up.
I completely agree @dr_yakupergun that this is strictly for adj chemo and not using this tool to decide on adj CDK4/6i! @drsarahsam for postmenopausal women node positive, do you mean N1 or N2? Or are you using this over OncotypeDx in any N+ postmenopausal women?
Results of OPTIMA Trial are important but follow up data reported is at 5 years only; however, we know that 50% of Patients with HR+ HER2- disease recurrences occur after 5 years. We may be comfortable applying it for patients with 4-5 involved LN and strongly positive ER.
I would be more likely to use in an N2 patient motivated to avoid chemotherapy.
Agree with @dr_yakupergun's approach. I would use in N2 especially when tumor characteristics are very Luminal-A(esque).
