[Slide 1]
X
OPTIMA design
Main eligibility criteria
Nodes: *0-9N+,
Women & men age >40 with excised breast cancer
minimum T-size requirement if NO/ N1mi
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ER-pos (IHC>10%) & HER2-neg
Neoadjuvant chemotherapy prohibited
Control arm
chemo.
endocrine
II
Prosigna*
informed
blinded to randomisation
1
R
consent
1
high score
chemo.
endocrine
Prosigna
ROR>60
Test-directed
RORS60
endocrine
low score
ET includes OFS for
All other treatment SoC
premenopausal patients
"Control - Prosigns testing used for analysis only UK control am losting performed following recrudinent completion
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---
[Slide 2]
IBCFS vs menopausal status: low ROR score
population
Premenopausal
Postmenopausal
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100
100
Invasive breast cancer free survival (%)
75
events
at 5 years
25
Control arm
25
Invasive breast cancer free survival (%)
75
HR 1.04; 95% CI 0.60-1.80
HR 1.14; 95% CI 0.76-1.71
50
50
No.
%IBCFS (95% CI)
No.
%IBCFS (95% CI)
events
at 5 years
25
95.5 (92.6-97.3)
Control arm
42
94.5 (92.2-96.2)
Test-directed arm
26
94.2 (91.0-96.2)
Test-directed arm
50
93.2 (90.6-95.0)
0
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Years from trial entry
Years from trial entry
Number -
Number at mk
Control
541
481
400
334
254
200
$40
Control
791
721
631
522
414
304
197
test described
559
487
410
347
256
195
as
lest directed
854
206
473
156
437
007
207
1.3% observed 5-year difference -favors chemotherapy
1.3% observed 5-year difference -favors chemotherapy
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[Slide 3]
Distant Recurrence Free Interval
V
Complete Per Protocol population
ROR <60 subpopulation
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100
100
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Distant recurrence free interval (%)
75
Adjusted HR 1.04; 90% CI 0.83-1.30
50
Distant recurrence free interval (%)
75
Adjusted HR 1.17; 90% CI 0.82-1.66
50
No.
%DRFI (95% CI)
No.
%DRFI (95% CI)
events
at 5 years
events
at 5 years
25
25
Control arm
104
94.1 (92.7-95.3)
Control arm
40
97.0 (95.6-98.0)
Test-directed arm
108
93.3 (91.7-94.5)
Test-directed arm
49
96.0 (94.5-97.1)
0
0
0
1
2
3
4
$
6
0
1
2
3
4
$
6
Years from trial entry
Years from trial entry
Number risk:
Number stank
Control
2050
1822
1968
1204
1904
744
489
Control
1358
1209
1046
665
676
507
340
Sest directed
2004
1863
1500
5311
993
732
487
test directed
1421
1262
1093
111
696
ses
346
0.8% observed 5-year difference -favors chemotherapy
1.0% observed 5-year difference -favors chemotherapy
Prof. Robert C. Stein
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[Slide 4]
Conclusions
OPTIMA has demonstrated that the 50-gene Prosigna test
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identifies a patient group with minimal if any chemotherapy benefit
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At most, 2 recurrences will be prevented for every 100 patients
The 50-gene test can assist safe adjuvant chemotherapy
decisions for:
premenopausal women aged at least 40 years treated with
ovarian function suppression
patients with 4 to 9 involved lymph nodes or stage IIIA tumors
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[Slide 1]
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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.
a pre-planned time-driven analysis
Robert C. Stein, Andreas Makris, lain R. Macpherson, Luke Hughes-Davies, Andrea
Marshall, Sarah E. Pinder, Abeer Shaaban, Karen J. Taylor, Carmel Conefrey, Mary
Rose Falzon, Bjorn Naume, Belinda Emma Kiely, David A. Cameron, Helena Margaret
Earl, Daniel William Rea, Peter S. Hall, Adrienne Morgan, Stuart McIntosh, John M.S.
Bartlett, Janet Dunn, OPTIMA Investigators and Trial Management Group
OPTIMA is registered as ISRCTN42400492 (US registry: NCT02027441)
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---
[Slide 2]
Patient and tumor characteristics (PP population)
Characteristic
Control arm
Test directed arm
Total
number PP
2059
2094
4153
age (range)
55 (40-84)
56 (40-82)
56 (40-84)
premenopausal
776 (38%)
775 (37%)
1551 (37%)
postmenopausal
1265 (61%)
1302 (62%)
2567 (62%)
men
18 (1%)
17 (1%)
35 (1%)
grade 1-2
1417 (69%)
1465 (70%)
2862 (69%)
grade 3
642 (31%)
629 (30%)
1271 (31%)
tumor size <30 mm
1104 (54%)
1128 (54%)
2232 (54%)
tumor size ≥30 mm
955 (46%)
966 (46%)
3050 (46%)
nodes: 0 / micromets
160 (8%)
167 (8%)
327 (8%)
1-3*
1515 (74%)
1534 (73%)
3049 (73%)
4-9
384 (18%)
393 (19%)
777 (19%)
*39% of pN1 tumors had a sentinel node biopsy only
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[Slide 3]
Invasive Breast Cancer Free Survival
Complete Per Protocol population
ROR ≤60 subpopulation
100
100
Invasive breast cancer free survival (%)
75
50
No.
%IBCFS (95% CI)
events
at 5 years
25
Invasive breast cancer free survival (%)
75
Adjusted HR 1.03; 90% CI 0.85-1.25,
Adjusted HR 1.06; 90% CI 0.80-1.40,
p(3%noninferiority) = 0.006
50
p(3.5%noninferiority) = 0.003
No.
%IBCFS (95% CI)
events
at 5 years
25
— Control arm
148
91.8 (90.1- 93.2)
— Control arm
68
94.8 (93.1- 96.1)
—
Test-directed arm
153
—
90.3 (88.5- 91.8)
Test-directed arm
76
93.6 (91.7- 95.0)
0
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Years from trial entry
Years from trial entry
Number atrisk:
Number atrisk:
Control
2059
1818
1563
1283
999
741
485
Control
1358
1207
1043
862
672
504
337
Test-directed
2094
1857
1591
1303
989
724
481
Test-directed
1421
1257
1086
905
694
503
342
Demonstrated non-inferiority limit = 2%
Demonstrated non-inferiority limit = 2%
No certainty of chemotherapy benefit
No certainty of chemotherapy benefit
1.5% observed 5-year difference -favors chemotherapy
1.2% observed 5-year difference -favors chemotherapy
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[Slide 1]
Conclusions - how does OPTIMA change my
clinical practice for early luminal BC ?
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1. I will now recommend a genomic assay for all post and premenopausal
women (>40 y) with any number of positive nodes
2. A "low risk" genomic test result will trigger shared decision-making
based on "trade-off" regarding CT Yes or No in the presence of optimal
endocrine therapy
Current knowledge indicates a very low (if any) CT benefit
independent of nodal burden and menopausal status
Some uncertainty remains in view of relatively small key sub
populations and short follow-up in the OPTIMA trial
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[Slide 1]
A lay summary of OPTIMA
The OPTIMA trial was designed to reduce unnecessary chemotherapy use for
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people with newly diagnosed hormone sensitive breast cancer.
OPTIMA recruited more than 4400 patients over 9 years from 6 countries.
The trial compared the number of breast cancer recurrences and deaths in patients
treated with standard chemotherapy with those having a chemotherapy decision
made using the Prosigna test. Everybody received hormone therapy.
Prosigna is a 50-gene test performed on cancer tissue removed at surgery.
OPTIMA showed that at most 2% of patients with low test-score tumors benefit from
chemotherapy. Everybody gets chemotherapy side-effects.
This includes premenopausal women aged 40 or older and patients with more than
3 involved lymph nodes.
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[Slide 1]
OPTIMA design
Main eligibility criteria
Nodes:
0-9N+,
Women & men age ≥40 with excised breast cancer
minimum T-size requirement if NO/ N1mi
ER-pos (IHC>10%) & HER2-neg
Neoadjuvant chemotherapy prohibited
Control arm
chemo.
endocrine
informed
1
R
consent
1
high score
chemo.
endocrine
Test-directed
Prosigna
ROR>60
ROR≤60
endocrine
low score
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[Slide 1]
Patients were recruited between January 2017 and December 2025
Trial flow
Randomized (n=4429)
Control arm (n=2215)
Test-directed arm (n=2214)
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Treatment not allocated by trial (n=50; 2.2%)
Treatment not allocated by trial (n=38; 1.7%)
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Ineligible (n=11) / declined treatment allocation
Ineligible (n=6) / declined treatment allocation (n=18)/
(n=23)/ withdrawal (n=16)
withdrawal (n=14)
Test failure - considered high score (n=11)
Test failure - considered high score (n=20)
*Non-luminal & ER-/HER2+ - other Rx (n=1)
*Non-luminal & ER-/HER2+ - other Rx (n=14)
Treatment allocation (n=2165; 97.7%)
Treatment allocation (n=2176; 98.3%)
Excluded from PP population (n=106 4.8%)
Excluded from PP population (n=82, 3.7%)
Ineligible (n=3)/ declined allocated treatment (n=71)/
Ineligible (n=5)/ declined allocated treatment (n=48)/
withdrawal (n=32)
withdrawal (n=29)
"Tumors with non-
Per-protocol population (n=2059; 93.0%)
Per-protocol population (n=2094; 94.6%)
luminal (HER2-enriched/
Basal-like) subtypes
underwent reflex ER &
HER2 testing. If found
*Other Rx
Chemo-endocrine
Chemo-endocrine
Endocrine therapy
"Other Rx
ineligible given tumor
appropriate treatment
(n=1)
therapy (n=2058)
therapy (n=660)
(n=1421)
(n=13)
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[Slide 1]
Statistical first results of OPTIMA
IBCFS Subgroup analysis in the low ROR population does not
suggest heterogeneity in the CT effect
Premenopausal patients
4-9 involved nodes
(N=1120)
(N=511)
-
79.
-
19
I
I
1.00
0.00-1.80
10
to
-
No
I
25
Control -
-
Central
Teld
R
-
R
.
.
-
1
.
5
.
$
.
.
:
2
1
.
$
.
-
from
I
hears entry
-
-
208
-
=
-
114
in
-
-
NOT
-
-
-
-
-
-
-
Observed 5-year chemotherapy benefit 13%
Observed 5-year chemotherapy benefit 1.6%
395 premenopausal patients reached 5 years follow-up
Caution: only 37 events total and 170 patients reaching
5 years follow-up
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[Slide 1]
The OPTIMA result
OPTIMA demonstrates that the 50-gene Prosigna test
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identifies a group of about 2/3 of patients with ER-positive
HER2-negative early breast cancer who do not have a
meaningful chance of benefit from adjuvant chemotherapy.
Our study population included women aged 40 or older and
patients with up to 9 involved lymph nodes.
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[Slide 1]
Endocrine therapy (ET)NOT INFERIOR to ET + Chemotherapy in
the presence of a favorable multigene expression assay*
N = 18,108 women recruited in 4 academic trials over 25 years
9y iDFS HR = 1.08
(95% CI 0.94 - 1.24)
Tailor-X(1) 2006-
5y DMFS for ET alone in High
Absolute difference= 1%
2010
clin/ low gen risk= 95.1%
(N= 6517 out of
(95% CI 93.1) 96.6%)
9719)
MINDACT (2)
OPTIMA(4)
2007 - 2011
Required:92%
2017-2025
(N= 2144 out of
5y iBCFS
(N=4429)
6693)
Overall HR 1.03 (90% CI
Randomized non inferiority trials
RX-ponder (3)
(power > 80%)
0.85-1.25) for control vs test
2011-2017
"Single arm" de-escalation trial
arm
(N= 5018)
Trial testing an interaction
Absolute difference= 1.5%
Node -
1-3N+ 1-9 N +
Increasing
tumor
burden
Non-significant interaction between
* ONCOTYPE DX®: Tailor-X RX, ponder
RS and CTX benefit (p= 0.35)
* MammaPrint®: MINDACT
Overall 5y iDFS (ET + CTX)
* Prosigna®: Optima
Absolute difference = 1.2%
(1) Sparano, NEJM 2018 (2) Piccart, Lancet 2021
(3) Kalinsky, NEJM 2021 (4) Stein, ASCO 2026
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OPTIMA asks a long-standing clinical de-escalation question: can biology-guided genomic testing safely spare adjuvant chemotherapy in women with clinically high-risk, node-positive 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 at the ASCO 2026 Plenary Session on May 30, 2026. Roughly 4,400 clinically high-risk patients were randomised. Patients found to be Prosigna ROR-low were randomised to omit adjuvant chemotherapy and receive endocrine therapy alone, versus the conventional standard of chemotherapy followed by endocrine therapy. 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, multicentre Phase III randomised non-inferiority trial (NCT02027441). Coordinated by Warwick Clinical Trials Unit and UCL. Eligible patients had Prosigna PAM50 testing performed on the primary tumour; those with a ROR score ≤60 ("low-risk" by PAM50 biology) were randomised 1:1 to test-directed therapy (omit adjuvant chemotherapy → endocrine therapy alone) versus standard-of-care (adjuvant chemotherapy followed by endocrine therapy). Patients with high-ROR tumours received chemotherapy and were not randomised.
Population
Clinically high-risk, ER+/HER2- early breast cancer, age ≥40, node-positive disease (1-9 involved nodes, including pN2). Both pre- and post-menopausal women were eligible. Approximately 4,400 patients enrolled across UK sites. Notably, this is a substantially higher-risk and more node-positive population than TAILORx or RxPONDER.
Assay
Prosigna 50-gene PAM50 Risk of Recurrence (ROR) signature (Veracyte). Test performed on primary tumour. Low-risk threshold pre-specified as ROR ≤60. Per the trial slides, approximately two-thirds of clinically high-risk patients were identified as Prosigna low-risk and therefore eligible for chemotherapy omission.
Primary Endpoint
5-year invasive breast cancer-free interval / distant disease-free survival in the ROR-low randomised cohort, with a pre-specified non-inferiority margin. Key secondary endpoints: distant recurrence, overall survival, quality of life, and treatment-related toxicity.
Test-Directed Strategy Met Non-Inferiority
At a median follow-up of 4 years, the 5-year IBCFS (invasive breast cancer-free survival) from the Kaplan-Meier curves 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 Prosigna ROR-low cohort (ROR ≤ 60, the population randomised to omit chemo), 5-year IBCFS was 94.8% control vs 93.6% test-directed, HR 1.06 (90% CI 0.80-1.40, p=0.003). Source: Stein et al., ASCO 2026 oral (Abstract #500); numbers per @stolaney1's verbatim post from the live presentation. The trial therefore supports the interpretation that, in clinically high-risk node-positive HR+/HER2- early breast cancer with a Prosigna low-ROR profile, adjuvant chemotherapy can be safely omitted in this biology subgroup.
Non-inferiority met — ROR-low cohort, 5-year outcomes
Clinical Reach — How Many High-Risk Patients Could Avoid Chemo
According to the trial slides shared by multiple KOLs (Nozawa, Griguolo, Lucarecco), the Prosigna ROR-low result identified roughly two-thirds (~68%) of clinically high-risk, node-positive ER+/HER2- patients as biologically low-risk — 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.
Nuance — The N2 Subgroup & Open Questions
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. Piccart's invited discussion framed OPTIMA as the first prospective demonstration that Prosigna can de-escalate chemotherapy in node-positive disease, but emphasised continued follow-up, longer-term recurrence data, and direct comparison with competing assays as outstanding questions. Several US-based KOLs (Hamilton, Tolaney) raised the practical question of how rapidly the Prosigna ROR-guided strategy will be adopted in a US market where Oncotype DX already dominates node-positive decision-making.
“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.”
Jules Bordet Institute · ASCO 2026 Invited Discussant
“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.”
