Spotlights on
prognostic genomic tests
Francesco Pantano MD, PhD Medical Oncology Department Campus Bio Medico of Rome
University Hospital
Let me start playing devil’s advocate…..
24% PRR in BCM
20% PRR in BCM
14% PRR in BCM
CMF vs no chemo CMF vs anthracycline Anthracycline vs
taxane/anthracycline
Yrs Breast Cancer Mortality, %
5253 women
RR: 0.76 (95% CI: 0.68-0.84) Log-rank 2P < .00001 10-yr gain: 6.2% (SE: 1.3)
No CTX 27.6%
CMF 21.5%
11.8%
15.3%
Yrs
9527 women
R: 0.80 (95% CI: 0.72-0.88) Log-rank 2P = .00001 10-yr gain: 4.1% (SE: 1.0)
CMF 24.1%
14.5%
11.5%
Anthracycline 20.0%
50 40 30 20 10 0
Yrs
Anthracycline 23.9%
16.7%
14.8%
11,167 women
RR: 0.86 (95% CI: 0.79-0.93) Log-rank 2P = .0005 8-yr gain: 2.8% (SE: 0.9)
Taxane + anthracycline 21.1%
Unfortunately….. Adjuvant Chemo works in HR+/HER2-
• Rough estimate: ~ 35% PRR in BC mortality for anthracycline/taxane regimen
– “Little affected by AGE, NODAL STATUS, TUMOR DIAMETER or DIFFERENTIATION(moderate or poor; few were well differentiated), ESTROGEN RECEPTOR STATUS, or TAMOXIFEN use”
Devil may say…..
It’s fine for me to treat all patients with
anthracycline/taxane
regimen
How can we save some patients from Al Pacino’s Bad Intents ?
How we can dentify patients who do not need adjuvant
chemotherapy because of their low risk of relapse?
The threshold displaying the
strongest prognostic significance for overall survival was
found to be > 25% cell staining (hazard ratio, [HR] 2.05;
95% CI, 1.7e 2.5; p < 0.00001).
What about Ki67 IHC Staining ?
….ooops
• Improve interlaboratory variation with assay standardisation.
• Establish an optimum cut-off point or evaluate the use of Ki67 as a continuous variable.
• Establish if different cut-off points are necessary for prognosis and therapy prediction.
• Evaluate the potential of automated image analysis for reducing between-assay variability
.NEED TO:
Some striking point about Ki67 IHC Staining
… need to move on….
Test Tissue required Molecule measured No. of analytes
uPA/PAI-1 Fresh/frozen Protein 2
Oncotype Dx FFPE mRNA 21
MammaPrint Fresh/frozen/FFPE mRNA 70
Prosigna FFPE mRNA 50+8
GGI FFPE mRNA 97
BCI FFPE mRNA 11
Mammostrat FFPE Protein 5
IHC4 score FFPE Protein 4
EndoPredict FFPE mRNA 11
Rotterdam signature Fresh/frozen mRNA 76
OncoMasTR FFPE mRNA 7
Curbest 95GC FFPE mRNA 95
… Breast Cancer Prognostic Signatures
Test ASCO NCCN ESMO St. Gallen group EGTM
uPA/PAI-1 LN− NR LN−, LN+ LN−, LN+ LN−
Oncotype DX LN− LN−, LN+ LN−, LN+ LN−, LN+ LN−, LN+
MammaPrint NR NR LN−, LN+ LN−, LN+ LN−, LN+
Prosigna LN− NR LN−, LN+ LN−, LN+ LN−, LN+
EndoPredict LN− NR LN−, LN+ LN−, LN+ LN−, LN+
BCI LN− NR NR LN−, LN+ LN−
NCCN guidelines discuss MammaPrint and Prosigna but do not specifically recommend either test.
ESMO and the St. Gallen group do not differentiate between lymph node–negative and lymph node–positive disease.
LN−, lymph node–negative; LN+, lymph node-positive (refers to 1–3 metastatic lymph nodes); NR, not recommended
Guidelines
• The majority were discovered and validated, lymph node negative patients Oncotype DX,
MammaPrint, Endo- Predict and Prosigna however, were also found to be prognostic in lymph node-positive patients (1-3 metastatic nodes)
• (uPA)/PAI-1, Oncotype DX and MammaPrint have to-date been evaluated for clinical value as part of a randomised prospective trial.
• Prosigna , EndoPredict and Genomic Grade Index, however, are currently undergoing evaluation in such trials.
Features Test
LN+; LN-; RCT Yes/Ongoing Prosigna MammaPrint Oncotype Dx EndoPredict LN-; RCT; Yes/Ongoing GGI
uPA/PAI-1
LN- Mammostrat
Rotterdam signature IHC4 score
Curbest 95GC BCI
OncoMasTR
Differences
• Additionally Prosigna EndoPredict, Breast Cancer Index (BCI) may be able to differentiate between patients with respect to their risk for early or late relapses following endocrine
• The value of Oncotype DX in predicting late distant recurrences is still unclear.
Features Test
LN+; LN-; Predict LR; RCT Yes/Ongoing Prosigna LN+; LN-; RCT Yes/Ongoing MammaPrint
Oncotype Dx EndoPredict
LN- RCT Yes/Ongoing GGI
uPA/PAI-1
LN-; Predict LR BCI
LN- Mammostrat
Rotterdam signature IHC4 score
Curbest 95GC OncoMasTR
Predict LR Endopredict
Late Recurrence Prediction
• All appear to provide prognostic information for relapse freesurvival independent of the traditional prognostic
factors such as tumour size, tumour grade and lymph node status.
• The most important genes in the multigene profiles for predicting patient outcome are those involved in cell proliferation.
• It is unclear whether the routine employment of
multianalyte tests leads to a better outcome for patients
Commonalities
None can currently be recommended for predicting the response to a specific
form of chemotherapy.
..and.. Surprise…
Oncotype Dx and Chemo Benefit
Oncotype Dx and Chemo Benefit
Evidence exists regarding the predictive ability of Oncotype DX in the high-risk group.
However:
• NSABP-B20 data are confounded by the dataset originally used to generate the assay.
• SWOG8814 data is hypothesis generating: small sample set and no additional prediction beyond 5
years.
Two large phase III prospective clinical trials (Tailor X and RxPonder) are evaluating the clinical utility of Oncotype DX as a predictive test in the following scenarios:
• TAILOR X: Patients with node-negative, HR+/HER2-negative disease with Intermediate RS (11-25).
• RXPONDER: Patients with 1-3 N+, HR+/HER2-negative disease with Low/Intermediate RS (≤25).
WHO ARE THESE PATIENTS?
• 2/3 pts with T≤ 2 cm
• (Only) 7% were G3
• 2/3 pts were post-menopausal
• 69% N+ =1 vs 5% N+ = 3
• 85% T≤ 2 cm
• 82% G1-G2
Overall 51% reduction in CT prescription
…News From San Antonio
Mammaprint and Chemo Benefit
Mammaprint and Chemo Benefit
• It was a noninferiority trial… (do you trust a noninferiority trial?)
• The aim of MINDACT, was not to predict a benefit from chemotherapy but rather to demonstrate that patients with a high clinical risk but a low genomic risk based on the MammaPrint have a favorable outcome (DMFS >92%) to justify not
treating them with chemotherapy
• If that's the case, why did you need a randomized prospective trial if that's all
you're powered to show? You could have done a single-arm trial and said that the DMFS is greater than 92% and you're done.”
Mammaprint and Chemo Benefit
• a benefit to chemotherapy on the DMFS endpoint in the genomically low-
risk/clinically high group was not out of the realm of possibility, with a P value of 0.080 and a hazard ratio of 0.60. On the endpoint of disease-free survival in this group, the difference of chemotherapy was statistically significant.
Mammaprint and Chemo Benefit..looking a little bit deeper in results
• In the clinically low-/genomic high-risk group, "you would expect
there to be a benefit from chemotherapy, and there was none.
Its primary test statistic is however not based on the randomization, so a prospective cohort study would have been sufficient to answer this objective.
If the two prediction models (CP model and gene signature) disagree in 32% of the patients, and if the treatment reduces 10-year mortality in the overall population from
24% to 20%, then the absolute difference in mortality between the two strategies is only 0.5%, and it has been calculated that 50 000 patients would be necessary to
identify this mortality difference in a statistically satisfactory manner
Mammaprint and Chemo Benefit
…News From San Antonio
• N=4,500
• HR+/HER2-negative pN1-2 or pT≥3 cm
• Non-inferiority (delta 3%, 85% power): 5-year DFS 82% without chemotherapy
• PROSIGNA will be used (cutpoint60): High risk vs Low/Intermediate risk
…News From San Antonio
P1: All High Risk Patients Should Be Treated With Adjuvant Chemotherapy P2: Multigene Test Better Define High Risk Patients
P3: Multigene Test Better Define Patients that Should be treated with Adjuvant Chemotherapy
Predictive Value of Multigene Tests.. Still
matter of deductive reasoning…
BIRD CAN FLY, I AM A BIRD, THEREFORE I CAN FLY
assuming that the preposition are true…
Campus Bio Medico of Rome University Hospital Experience
Prosigna@Campus Bio Medico of Rome
Starting from 2014 a fully operational Nanostring Ncounter Platform is available at Campus Bio Medico of Rome University.
• 146 Prosigna Tests have been performed
• 98 patients who had received Prosigna Test were clinically managed by Medical
Oncology Department.
Patient’s characteristics
T (mm)
ER%
PR%
KI67%
0 50 100
Number of values
Minimum 25% Percentile Median 75% Percentile Maximum
Mean Std. Deviation Std. Error of Mean
Lower 95% CI of mean Upper 95% CI of mean Sum
T (mm) 98
1.000 11.00 15.00 20.00 45.00
16.02 7.431 0.7506
14.53 17.51 1570
ER%
98
40.00 90.00 94.00 97.00 100.0
91.31 9.528 0.9625
89.40 93.22 8948
PR%
98
0.0 30.00 75.00 90.00 100.0
61.96 34.54 3.489
55.03 68.88 6072
KI67%
98
2.000 11.50 20.00 25.25 60.00
20.30 11.20 1.131
18.06 22.55 1989
71%
18%
9% 2%
NODE
0-Node 1-Node 2-Nodes 3-Nodes
16%
63%
21%
GRADING
G1 G2 G3
Let’s play a game
Can we be as informative as Prosigna test on Luminal A/B status using just
IHC staining ?
Let’s Start with ER
51% 49%
CONCORDANCE
Discordance Concordance
….Then we try with PR
39%
61%
CONCORDANCE
Discordance Concordance
And Finally…Ki67
27%
73%
CONCORDANCE
Discordance Concordance
Last Resort….Adding Grading
CONCORDANCE
Discordance Concordance
What’s the absolute benefit ?
ROR Score and Absolute Benefit of Adjuvant CT
R-Squared 0,2582 Pearson 0,5081 P-Value <0,001
The Cambridge Breast Unit (UK) uses the absolute 10-year survival benefit from chemotherapy to guide decision making for adjuvant chemotherapy as
follows: <3% no chemotherapy; 3-5% chemotherapy discussed as a
Change Decision
Concordance
Change Decision Concordance
• Prosigna test led to practice change in 20 out 98 patients
• Patients were treated with adjuvant chemotherapy as 15 pts were classified Luminal B (high/intermediate risk) and 5 pts Luminal A (high risk-node positive) whereas Predict suggested to abstain from chemotherapy.
Prosigna aided treatment decision
20% of Change Decision
Change Decision
Concordance
Change Decision Concordance
Change Decision
Concordance
Change Decision Concordance
