Pruebas genómicas de recurrencia en cáncer de mama - OncotypeDx y su entorno

Agosto 29, 2019
Bogotá, Colombia
Uso de Biomarcadores Genómicos para
Guiar Terapia Sistémica en EBC
Mauricio Lema Medina
Clínica de Oncología Astorga / Clínica SOMA, Medellín

BC
RE+
Her2-
N0
Surgery + HT
Cured
80-90%
Relapse
10-20%
No Chemo World

BC
RE+
Her2-
N0
Surgery + HT
Cured
80-90%
Relapse
10-20%
No Chemo World
BC
RE+
Her2-
N0
Surgery + HT +
Chemo
Cured
85-95%
Relapse
5-15%
Chemo World
Chemo decreases relapse in
5-8% Which ones?

The Oncotype DX Breast Recurrence
Score® Test
4
Tailoring Treatment for Early-Stage, ER-Positive, HER2-Negative
Breast Cancer in the Era of Precision Medicine

Adjuvant Therapy Recommendations for Breast Cancer in the Year 2000
……it is important to determine whether there are specific patient populations
for whom it is reasonable to avoid the administration of cytotoxic
chemotherapy. Unfortunately, very limited information is available to answer
this important question.
5
J Natl Cancer Inst. 2001.

NSABP B-20: Which ER-Positive Patients Benefit From Chemotherapy?
“…..statistical analyses failed to identify a
subgroup of patients with negative nodes
and ER-positive tumors who failed to
benefit from chemotherapy.“
Fisher et al. J Natl Cancer Inst. 1997.
Conclusions: When considered in conjunction with findings in other NSABP studies, results from B-20
indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, nodal status,
tumor size, or ER status, should be candidates for chemotherapy.
4-5% absolute benefit from chemotherapy
ER: estrogen receptor
TAM: tamoxifen
MFT: methotrexate, fluorouracil, tamoxifen
CMFT: cyclophosphamide, methotrexate, fluorouracil, tamoxifen
32-33% relative risk reduction with chemotherapy
6

Adjuvant Treatment Decisions Are Driven by Both Prognostic and
Predictive Factors
• Age
• Nodal status
• Tumor size
• Tumor Grade
• HER2
• ER/PR
• Other multigene signature assays
• Oncotype DX Breast Recurrence
Score® test
Prognostic factors: provide information on
outcomes (eg, recurrence rate)
• ER
• HER2
• Oncotype DX Breast Recurrence
Score test
Predictive factors: determine degree of
response to a specific therapy
7
Oncotype DX Breast Recurrence Score test is the only genomic assay that is both
prognostic and predictive of chemotherapy benefit
PR: progesterone receptor
HER2: human epidermal growth factor receptor 2Ballman. J Clin Oncol. 2015.

Treatment Decisions in ER-Positive, Node-Negative Invasive Breast Cancer
The Oncotype DX Breast Recurrence
Score® Test
8

Oncotype DX Breast Recurrence Score® Test
Paik et al. N Engl J Med. 2004.
9
ER
PR
Bcl2
SCUBE2
GRB7
HER2
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
Stromelysin 3
Cathepsin L2
GSTM1
CD68
BAG1
Beta-actin GAPDH RPLPO GUS TFRC
Estrogen Proliferation HER2 Invasion Others
5 Reference Genes
16 Breast Cancer–Related Genes
ORIGINAL CUTOFFS RS (0-100)
Low Risk RS (0-17)
Intermediate Risk RS (18-30)
High Risk RS (31-100)

The Recurrence Score® Prognostic Risk Groups Defined for
Distant Recurrence
NSABP B-14: First Validation Study for Prognosis in Node-Negative Patient Population
10
Paik et al. N Engl J Med. 2004.
Distant recurrence over time
10-year rate of recurrence = 6.8%*
95% CI: 4.0%, 9.6%
0 2 4 6 8 10 12 14 16
Years
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%Proportionwithoutdistantrecurrence
RS <18, n = 338
RS 18-30, n = 149
RS ≥31, n = 181
All Patients, n = 668
P < .001
10-year rate of recurrence = 14.3%
95% CI: 8.3%, 20.3%
10-year rate of recurrence = 30.5%*
95% CI: 23.6%, 37.4%
*10-year distant recurrence comparison between low- and high-risk groups: P <.001. RS: Recurrence Score result

The Breast Recurrence Score® Test Predicts Those Patients Who
Do and Do Not Derive Benefit From Chemotherapy
NSABP B-20: Second Validation Study for Prediction in Node-Negative Patient Population
Paik et al. J Clin Oncol. 2006. RS: Recurrence Score resultYears
PATIENTS WITH HIGH RS ≥31
28% absolute benefit from
tamoxifen + chemotherapy
Interaction P = 0.038
11
Events

5-Year BCSS by Recurrence Score® Group in the SEER
Database (= 49,681)
Miller et al. ASCO 2017.
Patients with Recurrence Score results 11-17 and 18-25 have excellent 5-year BCSS rates that are
remarkably similar to BCSS rates in Recurrence Score group 0-10
BCSS: breast cancer–specific survival
12

5-Year BCSS by Recurrence Score® Group and Reported
Chemotherapy Use in the SEER Population
13
Only small proportions of the RS results <1 (3%) and
RS results 11-17 (8%) groups reported CT use as ‘yes’
• 5-year BCSS was high, regardless of reported CT use
For the RS results 18-25 group, CT use reported as
‘yes’ was more common (29%)
• 5-year BCSS was 99% in this group, regardless of reported
CT use
For the RS results 26-30 and RS results ≥31 groups,
CT use reported as ‘yes’ was common
• 5-year BCSS was higher for those with CT use reported as
‘yes’ compared to ‘no/unknown’
BCSS: breast cancer–specific survival; RS: Breast Recurrence Score; CT: chemotherapyMiller et al. ASCO 2017.

TAILORx Takes the Oncotype DX Recurrence Score® Results to the
Next Level of Precision for Adjuvant Treatment Decisions
14
+
Prediction
of chemotherapy benefit
Prediction
of chemotherapy benefit
with precision for each patient
Prognosis
of disease
NSABP B-14 NSABP B-20 TAILORx
ORIGINAL CUTOFFS TREATMENT
Low (0-17) Endocrine (ET)
Intermediate (18-30) ET?
High (31-100) ET + chemo
RECURRENCE
SCORE
TREATMENT
Low (0-25) ET
High (26-100) ET + chemo
Sparano et al. J Clin Oncol. 2008.

5-Year BCSS in the Recurrence Score® Results 26-30 and 31-100
Groups by Reported Chemotherapy Use in the SEER Population
Miller et al. ASCO 2017.
15
Though not a randomized population, there is a clear and significant difference in 5-year BCSS in
patients receiving CT with RS results 26-100, supporting results seen in NSABP B-20
BCSS: breast cancer–specific survival

Rationale for Investigating Chemotherapy Benefit in Intermediate
Oncotype DX Recurrence Score® Results
16
Paik et al. J Clin Oncol. 2006.
TAM: tamoxifen
CMF: cyclophosphamide, methotrexate and fluorouracil
MF: cyclophosphamide, methotrexate and fluorouracil

Rationale for Adjusting Midrange Recurrence Score® Result to
11-25 for TAILORx Trial
• Minimize potential for
undertreatment
• RS (0-10) represent an
approximately 10% risk of
distant recurrence and
considered a threshold for
recommending chemotherapy
• Preserve chemotherapy
prediction in high-risk group
17
NSABP B-20: Relationship Between Continuous RS and Distant
Recurrence by Treatment RS: Recurrence Score result
TAM: tamoxifen
TAM
TAM + Chemo

Rationale for Adjusting Midrange Recurrence Score® Result to
11-25 for TAILORx Trial
NSABP B-20
18
Significant chemotherapy benefit with RS ≥26 similar to RS result ≥31
Patients 10-Year DRFS (%)
Recurrence by Addition
of Chemotherapy
RS No. % TAM TAM + chemo HR 95% CI P
0-10 177 27 98 95 1.788 0.360 to 8.868 0.471
11-25 279 43 95 94 0.755 0.313 to 1.824 0.531
26-100 195 30 63 88 0.285 0.148 to 0.551 < 0.0001
DRFS: distant recurrence-free survival
RS: Recurrence Score result
TAM: tamoxifen
Absolute Benefit = 25% Relative Risk Reduction = 71%

TAILORx Methods: Treatment Assignment and Randomization
Accrued Between April 2006–October 2010
19
HR+/HER2-Negative Node-Negative Breast Cancer
Oncotype DX® Test
(N = 10,273)
Arm A: Low RS 0-10
ET
(N = 1629)
Midrange RS 11-25
RANDOMIZE
(N = 6711)
Arm D: High RS 26-100
ET + Chemo
(N = 1389)
Arm B: Experimental Arm
ET Alone
(N = 3399)
Arm C: Standard Arm
ET + Chemo
(N = 3312) ET: endocrine therapy
HR: hormone receptor
HER2: human epidermal growth factor receptor 2
RS: Recurrence Score® result
Stratification factors:
• Menopausal status
• Planned chemotherapy
• Planned radiation
• RS 11-15, 16-20, 21-25

TAILORx Methods: Key Eligibility Criteria
Met NCCN Guidelines® for Recommending or Considering Adjuvant Chemotherapy
• Women with early-stage invasive breast cancer
• Age 18-75 years
• Node-negative
• ER- and/or PR-positive in local lab (before ASCO-CAP guidelines)
• HER2-negative in local lab
• Tumor size: 1.1-5.0 cm (or 0.6-1.0 cm and intermediate- or high-grade)
• Willing to have chemotherapy treatment assigned or randomized based on
Recurrence Score® results
20
Sparano et al. N Engl J Med 2018.
ASCO: American Society of Clinical Oncology
CAP: College of American Pathologists

TAILORx Design: Statistical Analysis Plan for Recurrence Score®
Result 11-25 Group
• Primary endpoint was invasive disease-free survival (iDFS)
• Secondary endpoints included distant recurrence-free interval, relapse-free interval, and
overall survival
• Noninferiority design for randomized arms
• Arm B: experimental (endocrine therapy alone) compared to Arm C: standard
of care (chemoendocrine therapy)
• Final analysis after 835 prespecified iDFS events were reached
21
Sparano et al. N Engl J Med 2018.

TAILORx: Patient Characteristics for Recurrence Score® Result 11-25 Group
22
Sparano et al. N Engl J Med. 2018.
Characteristic
Recurrence Score
Result of 11-25
Endocrine
Therapy (n =
3399)
Chemoendocrine
Therapy
(n = 3312)
Median Age
(Range) – years
55
(23-75)
55
(25-75)
Tumor Size – cm
Median (IQR)
1.5
(1.2-2.0)
1.5
(1.2-2.0)
Tumor Grade
L – 29%
I – 57%
H – 13%
L – 29%
I – 57%
H – 14%
Clinical Risk
L – 74%
H – 26%
L – 73%
H – 27%
33% (N = 2216) ≤50 years
13% (N = 869) ≤1 cm (grade I/H)
63% (N = 4253) tumors 1-2 cm
24% (N = 1587) >2 cm
Clinical risk defined via modified Adjuvant! Online
• Low risk:
• Tumor size ≤3 cm and Grade 1
• High risk: All other cases with known values for
grade and tumor size

Patient Characteristics: Wide Range of Recurrence Score® Results
Seen Across Prognostic Clinicopathologic Features
23
Sparano et al. N Engl J Med 2018; ECOG (data on file).
Characteristic
All Patients
(n = 9719)
Recurrence Score
Result of 0-10
Recurrence Score
Result of 11-25
Recurrence Score
Result of 26-100
Endocrine Therapy
(n = 1619)
Endocrine
Therapy (n =
3399)
Chemoendocrine
Therapy
(n = 3312)
Chemoendocrine Therapy
(n = 1389)
Median Age
(Range) – years
56
(25-75)
58
(25-75)
55
(23-75)
55
(25-75)
56
(23-75)
Tumor Size – cm
Median (IQR)
1.5
(1.2-2.1)
1.5
(1.2-2.0)
1.5
(1.2-2.0)
1.5
(1.2-2.0)
1.7
(1.3-2.3)
Tumor Grade
L – 2512 (27%)
I – 5242 (56%)
H – 1676 (18%)
L – 34%
I – 59%
H – 7%
L – 29%
I – 57%
H – 13%
L – 29%
I – 57%
H – 14%
L – 7%
I – 43%
H – 50%
Clinical Risk
L – 6615 (70%)
H – 2812 (30%)
L – 78%
H – 22%
L – 74%
H – 26%
L – 73%
H – 27%
L – 43%
H – 57%
25% of patients with RS 0-25 have
clinical high-risk features
43% of patients with RS 26-100 have
clinical low-risk features

Age Distribution in TAILORx Patients Is Representative of
Invasive Breast Cancer Patients in the US Population
24
Sparano et al. N Engl J Med. 2018; SEER Database N-, HR+, HER2-.
TAILORx 2006-2010 SEER 2010*
Age
Distribution –
total no. (%)
RS 0-10 RS 11-25 RS 26-100 All Patients
9719 women 12836 women
≤40 years 58 (4%) 311 (5%) 79 (6%) 448 (5%) 654 (5%)
41-50 years 371 (23%) 1905 (28%) 330 (24%) 2606 (27%) 2700 (21%)
51-60 years 563 (35%) 2441 (36%) 512 (37%) 3516 (36%) 3631 (28%)
61-70 years 518 (32%) 1763 (26%) 395 (28%) 2676 (28%) 4250 (33%)
70-75 years 109 (7%) 291 (4%) 73 (5%) 473 (5%) 1601 (13%)
The frequency of younger patients is similar between TAILORx and SEER patients
*SEER patients reflect HR-positive, HER2-negative breast cancer patients with clinicopathologic characteristics consistent with women eligible for TAILORx.

Tumor Size Distribution in TAILORx Patients Is Representative of
Invasive Breast Cancer Patients in the US Population
25
Sparano et al. N Engl J Med. 2018; SEER Database. N-, HR+, HER2-.
TAILORx 2006-2010 SEER 2010*
Tumor Size
Distribution –
total no. (%)
9719 women 12836 women
T1
≤1 cm
(grade 2/3)
202 (12%) 869 (13%) 188 (14%) 1259 (13%) 2258 (18%)
1.1-2.0 cm 1018 (63%) 4253 (63%) 741 (53%) 6012 (62%) 6674 (52%)
T2
2.1-3.0 cm 297 (18%) 1265 (19%) 348 (25%) 1910 (20%) 2413 (19%)
3.1-4.0 cm 83 (5%) 241 (4%) 91 (7%) 415 (4%) 762 (6%)
≥4.1 cm 19 (1%) 81 (1%) 20 (1%) 120 (1%) 729 (6%)
Distribution of tumor size is similar between TAILORx and SEER patients

Tumor Grade Distribution in TAILORx Patients Is Representative
of Invasive Breast Cancer Patients in the US Population
26
TAILORx 2006-2010 SEER 2010*
Tumor Grade
Distribution –
total no. (%)
9719 women 12,530 women
Low 530 (34%) 1893 (29%) 89 (7%) 2512 (27%) 2748 (22%)
Intermediate 931 (59%) 3721 (57%) 590 (43%) 5242 (56%) 7100 (57%)
High 111 (7%) 884 (14%) 681 (50%) 1676 (18%) 2682 (21%)
Distribution of tumor grade is highly similar between TAILORx and SEER patients
Sparano et al. N Engl J Med. 2018; SEER Database. N-, HR+, HER2-.

TAILORx Results: Systemic Treatments for Recurrence Score®
Results 11-25, Arms B & C (N = 6711)
• Endocrine therapy
• Comparable adherence and duration in both arms
• Extended endocrine therapy (>5 years) – 35%
• Postmenopausal – included aromatase inhibitor in 91%
• Premenopausal – included ovarian suppression in 13%
• Chemotherapy
• Most common regimens were taxane and cyclophosphamide (56%) and
anthracycline-containing (36%)
27

TAILORx Results: Endocrine Therapy Alone Was Not Inferior to
Chemoendocrine Therapy in Patients With RS 11-25 (Arms B & C)
Primary Endpoint: 9-Year Invasive Disease-Free Survival (iDFS) in ITT Population
836 iDFS events after
median follow-up of
7.5 years
29
ITT: intent-to-treat
iDFS: invasive disease-free survival
RS: Recurrence Score® results
ET: endocrine therapySparano et al. N Engl J Med. 2018.

TAILORx Results: Patients With RS 11-25 (Arms B & C) Have a
Very Low Risk of Distant Recurrence
Secondary Endpoint: 9-Year Distant Recurrence-Free Interval in ITT Population
199 of 836 (23.8%)
were distant
recurrences
30
DRFI: distant recurrence-free interval
ET: endocrine therapy

TAILORx Results: Patients With RS 11-25 on Endocrine Therapy Alone (Arm B)
Have Equivalent Outcomes to Those on Chemoendocrine Therapy (Arm C)
Other Secondary Endpoints: ITT Population
31
RFI: relapse-free interval
OS: overall survival

TAILORx Results: Patients in Arms A, B & C With RS 0-25 Have ≤5%
Risk of Distant Recurrence at 9 Years
9-Year Event Rates – ITT Population: All Arms
32
RS: Recurrence Score® resultSparano et al. N Engl J Med. 2018.
Patients in Arm D experienced a
higher rate of distant recurrence
at 13% despite
chemoendocrine therapy

TAILORx Results: Exploratory Analysis in Clinical Subgroups to
Identify Chemotherapy Benefit in Recurrence Score®
Results 11-25
• Exploratory interaction tests were performed for subgroups that may derive chemotherapy benefit in
the Recurrence Score 11-25 group (ITT population)
• Exploratory analysis subgroups:
• Recurrence Score subgroups 11-15 vs 16-20 vs 21-25; 11-17 vs 18-25
• Clinicopathologic subgroups: tumor size, tumor grade, clinical risk category
• Menopausal status
• Age
33
Sparano et al. N Engl J Med. 2018. ITT: intent-to-treat

TAILORx Results: Exploratory Analysis of Chemotherapy
Treatment Interactions in Recurrence Score® Results 11-25 Arms
34
Recurrence Score result
11-15 vs 16-20 vs 21-25
11-17 vs 18-25
Tumor size (≤2 cm vs >2 cm)
Grade (low vs int vs high)
Menopausal status (pre vs post)
Clinical risk category (high vs low)
No statistically significant chemotherapy treatment interactions were found in any
of these subgroups

TAILORx Results: Exploratory Analysis of Chemotherapy
Treatment Interactions in Recurrence Score® Results 11-25
35
• There was a statistically significant chemotherapy treatment interaction with patient age
and Recurrence Score (RS) for invasive disease-free survival and recurrence-free interval
• Some chemotherapy benefit was seen in patients age ≤50 who had RS results 16-20 and RS
results 21-25
• There was no statistically significant chemotherapy treatment interaction seen with patient
age and RS results for distant recurrence-free interval
Invasive disease–free survival defined as the first event of distant recurrence, local–regional recurrence,
contralateral breast or other second primary cancer, or death without cancer recurrence.
Recurrence-free interval defined as all distant and local recurrences.
Distant recurrence-free interval defined as distant recurrences only.Sparano et al. N Engl J Med. 2018.

TAILORx Results: A Small Chemotherapy Benefit Is Seen in Women
≤50 Years (N = 3054) With Recurrence Score® Results 16-20 and 21-25
9-Year Freedom From Distant Recurrence
36
CT: chemotherapy
RS: Recurrence Score results
*These differences in distant recurrences, while not statistically significant, may be clinically significant.
* *

Implications for Clinical Practice Based on TAILORx Definitive
Results Using the Oncotype DX Breast Recurrence Score® Test
37
Recurrence Score Result
0-25 26-100
No Chemotherapy Benefit Chemotherapy Benefit
Node-negative, HR-positive, HER2-negative
HER2: human epidermal growth factor receptor 2Sparano et al. J Clin Oncol. 2008.

TAILORx: The Prediction of Chemotherapy Benefit With the
Oncotype DX Breast Recurrence Score® Test Is Largely Binary for
Patients >50 Years
38
Sparano et al. J Clin Oncol. 2008; Genomic Health (data on file). RS distributions in tested US N-, HR+, HER2- patients in 2017.
Subgroup Age >50 years
RS 0-10
No CT Benefit
RS 11-15
No CT Benefit
RS 16-20
No CT Benefit
RS 21-25
No CT Benefit
RS 26-100
CT Benefit
~85% of patients ~15% of patients
CT: chemotherapy

TAILORx: Precise Determination of Potential Chemotherapy Benefit
for Patients ≤50 Years With Breast Recurrence Score® Test
39
CT benefit for distant recurrence from Sparano 2018 ASCO presentation; Sparano et al. J Clin Oncol. 2008; Genomic Health (data on file). RS
distributions in tested US N-, HR+, HER2- patients in 2017.
Subgroup Age ≤50 years
RS 0-10
No CT Benefit
RS 11-15
No CT Benefit
RS 16-20
~1.6% CT Benefit
RS 21-25
~6.5% CT Benefit
RS 26-100
CT Benefit
~50% of patients ~23% of patients ~12% of patients ~15% of patients
CT: chemotherapy

Prospective Validation of the Oncotype DX Breast Recurrence
Score® (RS) Test in TAILORx Provides the Highest Level of
Evidence for Adjuvant Treatment Decisions
• The TAILORx study utilized the Oncotype DX Breast Recurrence Score test to
definitively prove that HR-positive, HER2-negative, node-negative patients with
RS results 0-25 do not benefit from chemotherapy
• Safely spares patients with RS results 0-25 from overtreatment, as they have excellent
outcomes with endocrine therapy alone
• Provides information on potential chemotherapy benefit for patients ≤50 years with
RS results 16-25
• Prognostic subgroups studied in TAILORx (ie, tumor size, tumor grade) do NOT
predict who will or will not benefit from chemotherapy
• Consistent findings with NSABP B-20 confirm recommendations for adjuvant
chemotherapy for patients with RS results 26-100 eliminating risk
for undertreatment
40
Paik et al. J Clin Oncol. 2006.; Sparano et al. J Clin Oncol. 2008.; Sparano et al. N Engl J Med. 2018.

41
Clinicopathologic Prognostic Factors With
the Oncotype DX Breast Recurrence Score®
Test

Quantitative ER Expression Is Only Modestly Correlated With
Recurrence Score® Results
Many highly ER-expressing tumors have Recurrence Scores 26-100
Kim et al. J Clin Oncol. 2011. ER: estrogen receptor
42

Clalit Registry: Using Clinical or Pathologic Factors to Determine Treatment
Can Result in Significant Under and Overtreatment
Characteristic (N = 1801)
RS 0-25
N = 1442 (80.1%)
RS 26-100
N = 359 (19.9%)
Age – years <50 (N = 295)
50-69 (N = 1184)
≥70 (N = 322)
226 (76.6%) 69 (23.4%)
959 (81%) 225 (19%)
257 (79.8%) 65 (20.2%)
Tumor Size – cm ≤1 (N = 400)
>1-2 (N = 996)
>2 (N = 393)
Unknown (N = 12)
346 (86.5%) 54 (13.5%)
803 (80.6%) 193 (19.4%)
284 (72.3%) 109 (27.7%)
9 3
Tumor grade 1 (N = 258)
2 (N = 907)
3 (N = 297)
Unknown/not applicablea (N = 339)
243 (94.2%) 15 (5.8%)
747 (82.4%) 160 (17.6%)
164 (55.2%) 133 (44.8%)
288 51
43
a59.8% of unknown tumor grade are invasive lobular carcinoma.Stemmer et al. npj Breast Cancer. 2017.

West German Study Group PlanB Study: A Distribution of Recurrence Score®
(RS) Results Seen Within All Ranges of Ki-67 Expression
Gluz et al. J Clin Oncol. 2016.
44
RS results had a week to
moderate positive correlation
with Ki-67
• RS results >25 are found in
samples with Ki-67 <20%
• RS results ≤25 found in
samples with Ki-67 >39%
Ki-67 expression is not
predictive of
chemotherapy benefit

The Breast Recurrence Score® Test Can Identify Patients With Favorable
Histologic Subtypes With Recurrence Scores® Results >25 That Could Benefit
From Chemotherapy
Tadros et al. Ann Surg Oncol. 2018.
45
N = 504,362 N = 49,819 N = 5,069 N = 25,329 N = 16,116 N = 4,159 N = 3,599 N = 1,897
3.2 – 12.1% of tumors
with favorable
histologic subtypes
have Recurrence Score
results >25

TAILORx: Clinicopathologic Features Do Not Predict
Chemotherapy Benefit
Characteristics Predictive of Chemotherapy Benefit?
Tumor size (≤2 cm vs >2 cm) No
Grade (low vs int vs high) No
Menopausal status (pre vs post) No
Clinical risk category (high vs low) No
TAILORx confirmed that clinicopathologic subgroups are not predictive
of chemotherapy benefit. Only the Breast Recurrence Score® test is both
prognostic and predictive of the magnitude of chemotherapy benefit
46

Clinical Risk*
Low High
Recurrence
Score
Results
0-25
(n = 8068)
75% 25%
26-100
(n = 1359)
43% 57%
TAILORx: Oncotype DX Breast Recurrence Score® Prevents Over-
and Undertreatment of Patients
47
Would have been
overtreated
*Low clinical risk defined by low grade and tumor size ≤ 3 cm, intermediate grade and tumor size ≤2 cm, and high grade and tumor size ≤1 cm;
high clinical risk defined as all other cases with known values for grade and tumor size.
Would have been
undertreated

Oncotype DX Breast Recurrence Score® Test Is the Only
Predictive Biomarker That Identifies the Right Treatment for the
Right Patient
• Clinical and pathologic factors are not predictive of chemotherapy benefit
• Oncotype DX Breast Recurrence Score test is the only biomarker shown to be
predictive of the magnitude of chemotherapy benefit
• There is only modest correlation between clinical or pathologic factors and the
Recurrence Score® result
• The Recurrence Score result identifies those patients in which tumor biology is
discordant with clinical and pathologic factors, providing definitive prognostic and
predictive information for adjuvant treatment decisions and avoiding under-
or overtreatment
48

The Oncotype DX Breast Recurrence Score® Test
49
Current Guideline and Staging
Recommendations

7th Edition Stage
Tumor Size
Nodal
Involveme
nt
Metastasis
2010-2017
Application of the New Staging Criteria to Breast Cancer
Creation of Prognostic Stage Groups Using Biomarkers
Hortobagyi et al. AJCC Cancer Staging Manual. 8th ed. https://cancerstaging.org/references-tools/deskreferences/Pages/Breast-Cancer-Staging.aspx. Accessed January 17, 2018.
50

Inclusion of Oncotype DX Breast Recurrence Score® Test
into AJCC 8th Edition Staging Manual
When Oncotype DX Score is less than 11…*
51
Hortobagyi et al. AJCC Cancer Staging Manual. 8th ed. https://cancerstaging.org/references-tools/deskreferences/Pages/Breast-Cancer-Staging.aspx. Accessed January 17, 2018.
When TNM is… And G is… And HER2 Status is… And ER Status is… And PR Status is…
The Prognostic Stage
Group is…
T1 N0 M0
T2 N0 M0
Any Negative Positive Any IA
*If available.
“Oncotype DX® is the only multigene panel included to classify Pathological Prognostic
Stage because prospective Level I data support this use for patients with a score <11.”
(Emphasis added.)
— AJCC 8th Edition Cancer Staging Manual (Second Revision)

The Oncotype DX Breast Recurrence Score® Test Is the Only Multigene Assay
Incorporated in Major Guidelines for Prediction of Adjuvant Chemotherapy Benefit
52
Quantifies risk of recurrence as a continuous variable and predicts
responsiveness to adjuvant tamoxifen and chemotherapy
NCCN Guidelines®
0.5 cm, node-negative, N1mi
May be considered for select node-
positive (1-3 LN) patients
St. Gallen
Node-negative, node-positive
Provides not only prognostic but also predictive information regarding the
utility of cytotoxic therapy in addition to endocrine therapy
NCCN and NCCN Guidelines are trademarks of the National Comprehensive Cancer Network. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2018.
© National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed [March 20, 2018]. To view the most recent and complete version of the guideline, go online to NCCN.org. ASCO is a trademark of the American
Society of Clinical Oncology. NCCN, ASCO, ESMO, St. Gallen, NICE, and IQWiG do not endorse any product or therapy.
NCCN Clinical Practice Guidelines in Oncology. V.3.2018; Harris et al. J Clin Oncol. 2016; Krop et al. J Clin Oncol. 2017; Curigliano et al. Ann Oncol. 2017; NICE Diagnostics Guidance10. 2013; German Institute for Quality and
Efficiency in Health Care (IQWiG) Press Release, 5 September 2018; Senkus et al. Ann Oncol. 2015.
ASCO® Guidelines
Node-negative
Predicts the risk of recurrence and may be used to identify patients likely to
benefit from adjuvant tamoxifen or chemotherapy
NICE Diagnostics Guidance
Node-negative
Recommended as an option for guidance of adjuvant chemotherapy
IQWiG
Node-negative
The only test that has sufficient evidence to guide breast cancer adjuvant
chemotherapy decisions
ESMO
Node-negative
May be used to gain additional prognostic and/or predictive information to
predict the benefit of adjuvant chemotherapy

Possible Considerations for Guideline and Staging Updates Based
on TAILORx Results in HR-Positive/HER2-Negative, Node-Negative
Breast Cancer Patients
• AJCC Staging: TAILORx provides current prognostic information for patients
treated with standard of care adjuvant therapies based on the
Recurrence Score® result
• 9-year distant recurrence ≤5% for RS 0-25 on endocrine therapy alone
• 9-year distant recurrence 13% for RS 26-100 on chemoendocrine therapy
• Treatment guidelines for the adjuvant setting
• Remove intermediate scores
• Endocrine therapy alone for RS 0-25
• Chemoendocrine therapy for RS 26-100
• Discuss chemotherapy options and potential benefit in patients ≤50 years with RS 16-25
53
Paik et al. J Clin Oncol. 2006; Sparano et al. J Clin Oncol. 2008; Sparano et al. N Engl J Med. 2015; Sparano et al. N Engl J Med. 2018.

Overview of Available Multigene Assays
How Do They Compare With the Oncotype DX Breast Recurrence Score® Test?
54

Prognostic Versus Predictive Biomarkers
• Prognostic biomarkers: A prognostic biomarker provides information on a
cancer outcome (eg, disease recurrence, disease progression)
• Predictive biomarkers: A biomarker is predictive if the treatment effect is
different for biomarker-positive patients compared with biomarker-
negative patients
• At least 2 comparison groups are needed (eg, 2 different treatment arms in a
randomized trial)
• Examples: HER2, ER
• To determine whether a biomarker is potentially predictive, a formal test for
an interaction between the biomarker, treatment group, and outcome must
be statistically significant (P <0.05)
Ballman. J Clin Oncol. 2015.
55

Agendia, Inc.
56
MammaPrint® (70-Gene Test)

Genomic Tests for Breast Cancer Are NOT the Same
Commercially Available Tests Are Not Interchangeable
1. Paik et al. N Engl J Med. 2004.; 2. Paik et al. J Clin Oncol. 2006.; 3. Bueno-de-Mesquita et al. Lancet Oncol. 2007.; 4. Mook et al. Breast Cancer Res Treat. 2009.; 5. Sapino et al. J Mol Diagn. 2013.
Oncotype DX® (21-gene assay) MammaPrint® (70-gene assay)
Quantitative gene expression by RT-PCR Microarray
Clinical validation populations: homogeneous
with inclusion of standard of care adjuvant endocrine
therapy when reporting recurrence risk
Clinical validation populations: heterogenous
without consideration of standard of care adjuvant
endocrine therapy in reporting recurrence risk
Prospectively validated for prognosis Prospectively validated for prognosis
Validated for predicting therapy benefit:
• Lack of chemotherapy benefit (RS 0-25)
• Significant chemotherapy benefit (RS 26-100)
• Endocrine therapy benefit based on quantitative ESR1
expression (ER)
No evidence for chemotherapy or endocrine
therapy prediction
Results provide:
Prognosis: Continuous score provides individualized
risk of recurrence
Prediction: Largely binary result for chemotherapy
prediction
Results provide:
Prognosis: Binary result as low/high-risk group with no
individualized risk estimate
Prediction: None
57

MammaPrint® Prognosis Profile From Validation Study
van’t Veer et al. Nature. 2002; van de Vijver et al. N Engl J Med. 2002.
MammaPrint Low Risk:
A “low-risk” MammaPrint result means that
a patient has on average a 10% chance
that her cancer will recur within 10 years
without any additional adjuvant treatment,
either hormonal therapy or chemotherapy.
MammaPrint High Risk:
A “high-risk” MammaPrint result means
that a patient has a 29% chance that her
cancer will recur within 10 years without
any additional adjuvant treatment, either
hormonal therapy or chemotherapy.
MammaPrint does not provide the individual’s risk of
recurrence. How low or high is their risk?
58

Subset of MammaPrint® Prognostic Validation Studies in
Heterogeneous Patient Populations
Study
Pre-
menopausal
Post-
menopausal
ER+ ER- LN+ LN- Prospective
van de Vijver. N Engl J Med. 2002
(n = 295)
X X X X X
Buyse J. Natl Cancer Inst. 2006
(n = 307)
X X X X
Bueno-de-Mesquita. Lancet Oncol. 2007
(n = 427)
X X X X X
Mook. Breast Cancer Res Treat. 2009
(n = 241)
X X X
Wittner. Clin Cancer Res. 2008 (n = 100) X X X X X
Mook. Ann Oncol. 2010 (n = 148) X X X X X
Cardoso. N Engl J Med. 2016
(n = 1550)*
X X X X X X X
Adapted from Hyams et al. J Surg Oncol. 2016.
*High clinical risk/low genomic risk target population.
LN: lymph node
AET: adjuvant endocrine therapy
ACT: adjuvant chemotherapy
59

Prognostic Risk Assessment Data
MINDACT
60

MINDACT Results Summary
• The primary objective was met: patients with high clinical risk, low genomic risk
(by MammaPrint®) had a 5-year DMFS rate of 94.7% (95% CI, 92.5 to 96.2) without
chemotherapy
• Patients identified as Genomic High Risk by MammaPrint randomized to
chemotherapy did not show a therapeutic benefit
• Patients identified as Genomic Low Risk by MammaPrint randomized to
chemotherapy did show a consistent therapeutic benefit
• Results with node-positive patients with high clinical risk, low genomic risk are not
clear or definitive
61
Cardoso et al. N Engl J Med. 2016. DMFS: distant metastasis-free survival

MINDACT: Study Design
Enrollment
N=6693
Clinical Risk (C)
Adjuvant! Online
Genomic Risk (G)
70-gene signature
MammaPrint® (MMPT)
C-low/G-low (MMPT low)
N=2745
C-low/G-high (MMPT high)
N=592
C-high/G-low (MMPT low)
N=1550
C-high/G-high (MMPT high)
N=1806
Discordant
Randomized ChemotherapyNo Chemotherapy
Modified from Cardoso et al. N Engl J Med. 2016.
“We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene
signature to standard clinical–pathological criteria in selecting patients for adjuvant chemotherapy.”
62

MINDACT
High Clinical Risk
Low Genomic Risk
Randomize
Chemotherapy No Chemotherapy
Endpoint: 5-yr DMFS

MINDACT Primary Objective Defined
• In patients with high clinical risk, low genomic risk (MammaPrint® low), and
who did not receive chemotherapy:
• Is the lower boundary of the 95% confidence interval for the rate of
5-year distant metastasis-free survival 92% (ie, the noninferiority
boundary) or higher?
Cardoso et al. N Engl J Med. 2016.
Though discordant groups were randomized to endocrine
therapy alone or chemoendocrine therapy, the primary
objective was NOT to determine who does or does not
benefit from chemotherapy
65

MINDACT: Enrollment and Risk Groups Included in the Analyses
Only 644 out of 6693 Patients Were Used in the Primary Analysis
Enrollment
N = 6693
344 assigned to
receive chemo
346 not assigned to
receive chemo
2634 had C-low and G-
low at enrollment
(2745*)
690 had CLINICAL LOW RISK
and genomic high risk at
enrollment (592*)
1497 had CLINICAL HIGH RISK
and Genomic low risk at
enrollment (1550*)
1873 had C-high and
G-high at enrollment
(1806*)
*Number of patients in this group after lab
error correction applied
R
749 assigned to
receive chemo
748 not assigned to
receive chemo
R
53 had a change in
risk
42 received
chemotherapy
4 were ineligible
57 had a change in risk
76 received chemotherapy
5 had unknown chemotherapy
status
4 were ineligible
26 had a change in
risk
128 received
chemotherapy
9 had unknown
chemotherapy status
11 were ineligible
21 had a change in
risk
85 received
chemotherapy
1 had unknown
chemotherapy status
12 were ineligible
224 were included in
the per-protocol
population
the per-protocol
population
the per-protocol
population
the per-protocol
population
644 were included
in the primary-test
population
Per protocol
population
Genomic high (G-high): MammaPrint® high risk
Genomic low (G-low): MammaPrint low risk
66

MINDACT: Enrollment and Risk Groups Included in the Analyses
Only 644 out of 6693 Patients Were Used in the Primary Analysis
Enrollment
N = 6693
344 assigned to
receive chemo
346 not assigned to
receive chemo
2634 had C-low and G-
low at enrollment
(2745*)
690 had CLINICAL LOW RISK
and genomic high risk at
enrollment (592*)
1497 had CLINICAL HIGH RISK
and Genomic low risk at
enrollment (1550*)
1873 had C-high and
G-high at enrollment
(1806*)
*Number of patients in this group after lab
error correction applied
R
749 assigned to
receive chemo
748 not assigned to
receive chemo
R
53 had a change in
risk
42 received
chemotherapy
4 were ineligible
57 had a change in risk
76 received chemotherapy
5 had unknown chemotherapy
status
4 were ineligible
26 had a change in
risk
128 received
chemotherapy
9 had unknown
chemotherapy status
11 were ineligible
21 had a change in
risk
85 received
chemotherapy
1 had unknown
chemotherapy status
12 were ineligible
the per-protocol
population
the per-protocol
population
the per-protocol
population
the per-protocol
population
644 were included
in the primary-test
population
Intent-to-treat
population
Per protocol
population
Genomic high (G-high): MammaPrint® high risk
Genomic low (G-low): MammaPrint low risk
67

Patient Characteristics
Clinical High/Genomic Low
(MammaPrint® Low) Risk
(N=1550)*
TAILORx Recurrence
Scores® 11-25
(N=6711)
Age - yr
<50
≥50 to 70
>70
34.5% (N=534)
64.5% (N=1000)
1% (N=16)
33% (N=2216)
62.5% (N=4204)
4.5% (N=291)
Tumor size
<1 cm
1-2 cm
>2 cm
2.5% (N=38)
39.4% (N=610)
58.1% (N=843)
13% (N=869)
63% (N=4253)
24% (N=1587)
Tumor grade
Grade 1
Grade 2
Grade 3
6.3% (N=98)
64.2% (N=995)
28.6% (N=443)
29% (N=1893)
57% (N=3721)
14% (N=884)
Lymph node status
N0
N1
N2
52.4% (N=812)
47.2% (N=732)
0.4%(6)
100% (N=6711)
0%
0%
Hormone receptor
status
ER+, PR+ or both
ER- and PR-
98.1% (N=1520)
1.9% (N=29)
100% (N=6711)
0%
HER2 status%
HER2-
HER2+
91.8% (N=1423)
8% (N=124)
100% (N=6711)
0%
Patient Populations: TAILORx Has a Larger, Homogenous Patient Population
Compared to MINDACT
*Patient characteristics are not provided for the primary test population (N=644).
68

Click to edit Master title style Click to edit Master title style
MINDACT: Primary Objective Was Met
5-Year Rate of Distant Metastasis–Free Survival (DMFS)
Primary Objective:
In patients with high clinical risk, low genomic
risk (no chemotherapy), is the lower boundary
of the 95% confidence interval (CI) for the
rate of 5-year DMFS 92% or higher?
Yes, patients not treated with chemotherapy
(CT) had a 5-year DMFS rate of: 94.7% (95%
CI, 92.5 to 96.2)
Heterogeneous primary test population:
• N0, N1, N2
• ER/PR+, ER-/PR-
• HER2+ & HER2-
Cardoso et al. N Engl J Med. 2016.; Piccart et al. AACR. 2016.
CI: confidence interval
69

Hormone Receptor–Positive/Node-Negative Population
MINDACT
70

Clinical Risk Group Definitions in MINDACT
Clinical risk was defined in the MINDACT trial via a modified Adjuvant! Online score
HR-positive, HER2-negative, node-negative
Low-risk:
Tumor size <3 cm and Grade 1
High-risk:
All other cases with known values for grade and tumor size
71

MINDACT: MammaPrint® Has Not Been Show to be Predictive of
Chemotherapy Benefit in Node-Negative Patients – ITT Population
DMFS: distant metastasis–free survival
ITT: intent-to-treat population
CT: chemotherapy
CI: confidence interval
N=666 patients
Despite high-risk MammaPrint results,
patients receive no benefit from
chemotherapy
Despite low-risk MammaPrint results,
patients show a trend towards chemotherapy
benefit (31% risk reduction)
N=787 patients
(MammaPrint Low) (MammaPrint High)
72

Low-Risk MammaPrint® Patients Showed a Consistent Improvement When
Randomized to Chemotherapy – ITT Population
Clinical High-Risk/Genomic Low-Risk (MammaPrint® Low)
29% relative risk reduction
Chemotherapy
No Chemotherapy
Year Disease-Free Survival CT
Patients
(N)
Events
(O)
% at 5 yr
(95% CI)
Hazard Ratio
(95% CI)
P-value
Clinical high-risk Yes 749 54 92.9 (90.5-94.7) 0.71 (0.50-1.01) 0.055
MammaPrint low-risk No 748 78 90.1 (87.5-92.1) 1.00
MammaPrint low-risk patients
experience a disease-free
survival benefit from
chemotherapy
~3%
absolute benefit
ITT: intent-to-treat population
CT: chemotherapy
CI: confidence Interval
73

Patients With Low-Risk MammaPrint® Results Showed a
Consistent Improvement When Randomized to Chemotherapy
Risk Group, Outcome,
and Treatment Strategy*
Chemotherapy
No. of
Patients
No. of
Events
Percentage With Outcome
of 5 Years (95% CI)
Hazard Ratio
(95% CI)
P-Value
Clinical high-risk and
genomic low-risk
DMFS 35% relative risk reduction
Disease-free survival
Overall survival
Adapated from Cardoso et al. N Engl J Med. 2016.
*Per-protocol population. CI: confidence interval
DMFS: distant metastasis-free survival
74

MammaPrint® 2017 ASCO® Guidelines Based on MINDACT Data
Guideline Patient Population Recommendation
1.1.1 ER/PR+, HER2-, node-negative, high
clinical risk
May use to withhold adjuvant systemic chemotherapy
1.1.2 ER/PR+, HER2-, node-negative,
low clinical risk
Should not be used to withhold adjuvant systemic chemotherapy
(did not appear to benefit even with genomic high risk)
69% of HR+/HER2-/node-negative patients included in MINDACT
were clinically low risk and not eligible for MammaPrint® testing
Only 30.9% of HR+/HER2-/node-negative patients included in MINDACT were
clinically high risk and eligible for MammaPrint® testing
Krop et al. J Clin Oncol. 2017.; Cardoso et al. N Engl J Med. 2016.
75

Study Comparison – MINDACT & TAILORx
In ER-Positive, HER2-Negative, Node-Negative Patients
TAILORx MINDACT
Primary Objective Randomized Chemo Benefit Prognosis
Evaluable Patients (Primary Objective) 6711 350
Clinical Risk (%)
Low
High
75%
25%
69%
31%
Genomic Risk (%)
Low
High
86%
14%
75%
25%
Median Follow-up (years) 7.5 5.0
Reported Outcomes (years) 9 5
Sparano et al. N Engl J Med. 2018; Cardoso et al. N Engl J Med. 2016.
76

Risk Stratification by Oncotype DX Breast Recurrence Score® and
MammaPrint® in the Same Patient Cohorts
Assay Concordance
77

82.1%
36.1%
61.4%
29.4%
17.9%
34.5%
38.6%
OPTIMA Study Stratified Risk Comparing Oncotype DX Breast
Recurrence Score® Test With Other Prognostic Multigene Assays
in the Same Patients
Oncotype DX
Breast Recurrence
Score assay
0-25 26-100Recurrence Score® (RS) results:
Low Intermediate HighRisk categories:
Prosigna
MammaPrint
Adapted from: Bartlett et al. J Natl Cancer Inst. 2016.
Pooled risk group distributions, N = 313 early-stage breast, node-negative and node-positive cancer patients
MammaPrint® assigns a substantially larger number of patients as high-risk
compared to Oncotype DX test, resulting in overtreatment with chemotherapy
Low Risk High RiskMammaPrint results:
78

Multigene Assays Do Not Classify Patients in The Same Way
MammaPrint® (genomic risk)
Low-Risk High-Risk Total
Oncotype DX Breast
Recurrence Score® (RS) test
RS 0-25 (Low) 177 70 247
RS 26-100 (High) 6 44 50
Total 183 114 297
Of 247 “low-risk” patients by RS result, 70 (28%) are high-risk by MammaPrint
Potential for
overtreatment
Of 50 “high-risk” patients by RS result, 6 (12%) are low-risk by MammaPrint
Potential for
undertreatment
Concordance between the two assays is 74%;
MammaPrint consistently classifies more patients as high risk
79
Adapted from: Bartlett et al. J Natl Cancer Inst. 2016.

Many Patients Stratified as High Risk by MammaPrint® Have High
Estrogen Receptor (ER) Expression by Oncotype DX Breast
Recurrence Score® Test
Poulet et al. SABCS 2012.
Many patients with high ER expression
and low-risk Oncotype DX Recurrence
Score® results are classified as high
risk by MammaPrint
MammaPrint high-risk classification is
not based on ER expression or
standard-of-care treatment with
adjuvant endocrine therapy
Patients stratified as high risk by
MammaPrint with high quantitative ER
expression may have a low risk of
recurrence with appropriate hormone
therapy
ER Expression by MammaPrint Risk Category
High
Intermediate
Low
Recurrence
Score Result
80

Multiple Studies Consistently Show MammaPrint® Classifies
37%-56% of ER-Positive, HER2-Negative Patients as “High Risk”
Denduluri et al. J Clin Oncol. 2011.; Cloughet al. St. Gallen 2013.; Shivers et al. SABCS 2013.; Marounet al. J Clin Oncol. 2015.; Dabbs et al. J Clin Oncol. 2017.; Tsai et al. Jama Oncol. 2017.
Denduluri 2011
56%
High risk
Clough 2013
39%
High risk
Shivers 2013
47%
High risk
Maroun 2015
43%
High risk
Dabbs 2017
37%
High risk
Tsai 2017
56%
High risk
MammaPrint has NOT been proven to be predictive of chemotherapy benefit and
overclassifies patients as high risk, resulting in overtreatment with chemotherapy
81

Genomic Assays for Breast Cancer Are NOT the Same
1. Paik et al. N Engl J Med. 2004.; 2. Paik et al. J Clin Oncol. 2006.; 3. Filipits et al. Clin Cancer Res.2011
Oncotype DX® (21-gene assay) EndoPredict® (12-gene assay)
Quantitative gene expression by RT-PCR Quantitative gene expression by RT-PCR
Recurrence Score® (RS) – calculated from
gene expression only
EPclin® Risk Score – calculated from a
combination of gene expression, tumor size,
and nodal status
Prospectively validated for prognosis Validated for prognosis (no prospective data)
• Lack of chemotherapy benefit (RS 0-25)
• Significant chemotherapy benefit (RS 26-100)
• Endocrine therapy benefit based on quantitative
ESR1 expression (ER)
No evidence for chemotherapy or endocrine
therapy prediction
Results provide:
Prognosis: Continuous score provides
individualized risk of recurrence
Prediction: Largely binary result for
chemotherapy prediction
Results provide:
Prognosis*: Continuous score provides
Prediction: None
*Node-negative & -positive patients grouped in one report.
83

Endopredict® EPclin Algorithm Is Strongly Influenced by
Nodal Status
EPclin Risk Score = 0.35 T + 0.65 N + 0.28 (EP)
T = 1 for ≤1 cm
T = 2 for 1–2 cm
T = 3 for 2–5 cm
T = 4 for >5 cm
N = 1 for N0
N = 2 for 1–3 nodes
N = 3 for 4–10 nodes
N = 4 for >10 nodes Reports classify prognosis within a mixed
N0-N2 population as “High- vs Low-Risk”
Tumor size
(Factor 1-4)
Nodal status
(Factor 1-4)
EP Molecular Score
EP Molecular
Score
(Factor 0-15)
The Oncotype DX Breast Recurrence Score® test is highly prognostic based on tumor
biology alone; additional prognostic factors are not required
Brase et al. Microarrays. 2013.
84

EndoPredict® Prognostic Validation Studies
Postmenopausal only;
32% are N+ patients
54% premenopausal;
N+ only
There are no validation data in N0 premenopausal patients or in
premenopausal patients treated with endocrine therapy alone
Buus et al.
comparison with
Oncotype DX®
N0: node-negative
N+: node-positive
85
Flipits et al. Clin Cancer Res. 2011; Martin et al. Breast Cancer Res. 2014; Buus et al. J Natl Cancer Inst. 2016.

Does EndoPredict® Provides Clarity on Adjuvant Therapy
Decisions?
• Relies on pathologic features for prognosis, most heavily on nodal status
• Vast majority of all node-positive patients are high-risk
• No prospective data
• Not shown to be predictive of chemotherapy benefit
• No data in node-negative premenopausal patients or with endocrine therapy alone
In node-negative patients and those with 1-3 positive nodes,
Oncotype DX Breast Recurrence Score® is highly prognostic based on
genomics (tumor biology) alone and is predictive of who will and who will
not benefit from chemotherapy
86
Flipits et al. Clin Cancer Res. 2011; Martin et al. Breast Cancer Res. 2014; Buus et al. J Natl Cancer Inst. 2016.

Risk Stratification by Oncotype DX Breast Recurrence Score® and
EndoPredict® in the Same Patient Cohorts
Assay Concordance
87

EndoPredict® EPclin Score and the Oncotype DX Breast Recurrence
Score® Test Do Not Identify the Same Patients as Low and High Risk
Moderate Correlation Between Assays (r = 0.45)
Varga et al. PLoS One. 2013.
N = 19 N = 15
Potential For Overtreatment:
Nearly half (47% or 7/15) of
patients identified as “high-
risk” by EPclin are “low-
risk” by Oncotype DX (RS 0-
25) and would receive no
benefit from chemotherapyN=15
N=10
N=9
Potential for Undertreatment:
21% (4/19) of patients identified
as “low-risk” by EPclin are
“high-risk” by Oncotype DX (RS
26-100) and would not receive
chemotherapy
RS: Recurrence Score
EPclin: EndoPredict molecular score + tumor size + nodal status
88

EndoPredict® Consistently Classifies 35%-52% of ER-Positive, HER2-
Negative Postmenopausal Patients as “High Risk” in Multiple Studies
These results are not consistent with known biology of ER-positive, HER2-negative breast cancer
EndoPredict does not have chemotherapy prediction data, resulting in potential overtreatment with
chemotherapy in many of the patients that are identified as high risk
89
Varga et al. PLoS One. 2013.; Buus et al. J Natl Cancer Inst. 2016.; Filipits et al. Clin Cancer Res. 2011.
EPclin Risk Score
Varga Study
44%
High risk
ABCSG6
52%
High risk
ABCSG8
35%
High risk
TransATAC
41%
High risk

90
Prosigna® Risk of Recurrence (ROR)
Score

Genomic Assays for Breast Cancer Are NOT the Same
1. Paik et al. N Engl J Med. 2004.; 2. Paik et al. J Clin Oncol. 2006.; 3. Dowsett et al. J Clin Oncol. 2013.; 4. Gnant et al. Ann Oncol. 2013.
Oncotype DX® (21-gene assay) Prosigna® (58-gene assay)
Quantitative gene expression by RT-PCR
Nanostring nCounter® – intrinsic subtyping and
gene expression
Recurrence Score® Result – calculated from gene
expression only in central laboratory
Risk of Recurrence (ROR) Score – correlates tumor
gene expression with PAM50 molecular profiles plus
tumor size in local pathology laboratory
Prospectively validated for prognosis Validated for prognosis (no prospective data)
- Lack of chemotherapy benefit (RS 0-25)
- Significant chemotherapy benefit (RS 26-100)
- Endocrine therapy benefit based on quantitative ESR1
expression (ER)
No evidence for chemotherapy or endocrine therapy
prediction
Results provide:
Prognosis: Continuous score provides
Prediction: Largely binary result for chemotherapy
prediction
Results provide:
Prognosis*: Continuous score provides
individualized risk of recurrence; risk groups for node-
negative (L/I/H) and node-positive (L/H)
Prediction: None
91

Prognosis with Prosigna® Risk of Recurrence (ROR) Score
Combines Intrinsic Subtyping with Gene Expression and Tumor Size
Patient’s tumor gene expression profile is
compared to PAM50 molecular profiles
(centroids) to determine degree of correlation
Dowsett et al. J Clin Oncol. 2013.; Gnant et al. Ann Oncol. 2013.
Correlation to PAM50 profile is combined
with proliferation score and tumor size to
generate an ROR Score
92

Prosigna® Studies Prove That the Risk of Recurrence (ROR) Score is
Prognostic Only and Have NOT Shown to be Predictive of
Chemotherapy Benefit
Study Treatment
Pre-
menopausal
Post-
menopausal
ER+ ER- LN+ LN- Prognostic
Chemo
Prediction
Jensen. Breast Cancer Res.
2018 (n = 460)
C, CMF, or
untreated
X X X X X Yes No
Liu. npj Breast Cancer. 2016
(n = 1311)
ACT X X X X X Yes No
Liu. Breast Cancer Res Treat.
2015 (n = 1094)
CEF, AC/T or
EC/T
X X X X X X No No
Gnant. Annals of Oncol. 2014
(n = 1478)
TAM or
TAM/AI
X X X X Yes N/A
Dowsett. J Clin Oncol. 2013
(n = 1017)
TAM or AI X X X X Yes N/A
l
LN: lymph node
CMF: cyclophosphamide, methotrexate, fluorouracil
ACT: doxorubicin, cyclophosphamide, paclitaxel
CEF: cyclophosphamide, epirubicin, flurouracil
ECT: epirubicin, cyclophosphamide, paclitaxel
TAM: tamoxifen
AI: aromatase inhibitor
93

MA.21 Clinical Validation: Prosigna® Risk of Recurrence (ROR) Score
Is Neither Prognostic Nor Predictive of Chemotherapy Benefit
Liu et al. Breast Cancer Res Treat. 2015.
MA.21 Study
Luminal B vs A:
HR 1.20, 95% CI
0.90-1.80;
P = 0.37
In the MA.21 study, ROR Score and Luminal A/B subtypes were neither
prognostic nor predictive of chemotherapy benefit
(Interaction P = 0.23)
ROR
94

TransATAC: Prognostic Comparison of Prosigna® Risk of
Recurrence Score and Oncotype DX Breast Recurrence Score®
• Rate of distant recurrence is comparable between ROR and RS risk groups
• When compared by C Index, both scores are prognostic with the addition of the same clinical/pathologic
prognostic parameters (CTS = nodal status, tumor size, grade, age, AI/TAM treatment)
Dowsett et al. J Clin Oncol. 2013.
(< 10% risk)
gene expression + tumor size
gene expression only
gene expression + clin/path
(10%-20% risk)
(> 20% risk)
(10%-20% risk)
(> 20% risk)
(< 10% risk)
ROR: Risk of Recurrence Score
CTS: clinical treatment score
95

Prosigna® Risk of Recurrence (ROR) Score and Intrinsic Subtypes in
Premenopausal Patients Randomized to No Treatment or
Chemotherapy (N = 460)
Jensen et al. Breast Cancer Res. 2018.
Disease-Free Survival (DFS)
Though continuous ROR score was prognostic in
untreated patients (DFS, P <0.001), there was no
statistically significant interaction between ROR risk
groups and chemotherapy treatment
Prosigna ROR Score and Luminal A/B subtypes are not predictive of
chemotherapy benefit in ER-positive/HER2-negative patients
A significant interaction was observed between
intrinsic subtypes and chemotherapy treatment for
DFS (Pinteraction = 0.003), due to a pronounced effect
in basal-like subtype, not ER+/HER2-negative
DFS: disease-free survival
96

Does Prosigna® Risk of Recurrence (ROR) Provide Clarity on
Adjuvant Therapy Decisions?
• Relies on pathologic features to improve its prognostic value
• Validated in heterogeneous patient populations
• No prospective data
• Not shown to be predictive of chemotherapy benefit
In N0 and N1 patients, Oncotype DX Breast Recurrence Score® test is
highly prognostic based on genomics (tumor biology) alone and
predictive of who will and who will not benefit from chemotherapy
97
Jensen et al. Breast Cancer Res. 2018.; Liu et al. npj Breast Cancer. 2016.; Liu et al. Breast Cancer Res Treat. 2015.; Gnant et al. Annals of Oncol. 2013.; Dowett et al. J Clin Oncol. 2013.

Risk Stratification by Oncotype DX Breast Recurrence Score® and Prosigna®
in the Same Patient Cohorts
Assay Concordance
98

Poor Correlation: The Oncotype DX Breast Recurrence Score® and
Prosigna® Results in Node-Negative Patients
Correlation Between Tests Is Poor (Spearman 0.08)
Alvarado et al. Adv Ther. 2015.
Of the node-negative patient samples classified as high risk by Prosigna, 57% (4/7 samples)
had low Recurrence Score® results and would be overtreated with chemotherapy
Recurrence Score = 25
99

Multiple Studies Consistently Show Prosigna® Risk of Recurrence
(ROR) Score Classifies >26% of ER-Positive, HER2-Negative
Patients as “High Risk”
Dowsett et al. J Clin Oncol. 2013.; Filipits et al. Clin Cancer Res. 2014.; Lænkholm et al. J Clin Oncol. 2018.
TransATAC
26%
High risk
ABCSG8
34%
High risk
Danish Registry
42%
High risk
The Prosigna ROR Score has been proven NOT to be predictive of chemotherapy benefit
and overclassifies patients as high risk, resulting in overtreatment with chemotherapy
100

Trial Assigning IndividuaLized Options
for TReatment (TAILORx)
Phase 3 trial of chemoendocrine therapy versus endocrine therapy alone in
HR-positive, HER2-negative, node-negative breast cancer and an
intermediate prognosis 21-gene Recurrence Score®
101

Prospective Validation of the Breast Recurrence Score® Test in TAILORx
Provides the Highest Level of Evidence for Adjuvant Treatment Decisions
• The TAILORx study utilized the Oncotype DX Breast Recurrence Score® (RS) test to
definitively prove that HR-positive, HER2-negative, node-negative patients with RS
results 0-25 do not benefit from chemotherapy
• Safely spares patients with RS results 0-25 from overtreatment, as they have excellent outcomes with
endocrine therapy alone
• Provides information on potential chemotherapy benefit for patients ≤50 years with
RS results 16-25
• Prognostic subgroups studied in TAILORx (ie, tumor size, tumor grade) do NOT predict
who will or will not benefit from chemotherapy
• Consistent findings with NSABP B-20 confirm recommendations for adjuvant
chemotherapy for patients with RS results 26-100 eliminating risk for undertreatment
103
Paik et al. J Clin Oncol. 2006.; Sparano et al. J Clin Oncol. 2008.; Sparano et al. N Engl J Med. 2018.

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