The Trial Assigning IndividuaLized Options for Treatment (Rx) -TAILORx,TAILORx clinical trial showed that most women with hormone receptor (HR)–positive, HER2-negative, axillary node–negative early-stage breast cancer and a mid-range score on a 21-tumor gene expression assay (Oncotype DX® Breast Recurrence Score) do not need chemotherapy after surgery

1. Tailorx Trial – Journal Club
DR.BHAVIN VADODARIYA
DNB Surgical Oncology Resident,
Apollo CBCC Cancer Care,
Ahmedabad
Date-17/07/2018

3. Introduction
• Breast cancer is the most common cancer in women in the
United States and worldwide.
• Hormone-receptor–positive, axillary node–negative disease
accounts for approximately half of all cases of breast cancer
in the United States.
• Adjuvant chemotherapy reduces the risk of recurrence, with
effects that are proportionally greater in younger women but
that are little affected by nodal status, grade, or the use of
adjuvant endocrine therapy.

4. These findings led a National Institutes of Health consensus
panel to recommend adjuvant chemotherapy for most
patients, a practice that has contributed to declining breast
cancer mortality. However, the majority of patients may
receive chemotherapy unnecessarily.

5. *The 21-gene recurrence-score assay (Oncotype DX, Genomic
Health) is one of several commercially available gene-
expression assays that provide prognostic information in
hormone-receptor–positive breast cancer.
*The recurrence score based on the 21-gene assay ranges from
0 to 100 and is predictive of chemotherapy benefit when it is
high, whether a high score is defined as 31 or higher or 26 or
higher; when the recurrence score is low (0 to 10), it is
prognostic for a very low rate of distant recurrence (2%) at 10
years that is not likely to be affected by adjuvant
chemotherapy.

6. Although expert panels recommend the use of the 21-
gene assay, uncertainty remains as to whether
chemotherapy is beneficial for the majority of
patients, who have a mid-range recurrence score.
.

7. The Trial Assigning Individualized Options for
Treatment (TAILORx) was designed to address
these gaps in our knowledge by determining
whether chemotherapy is beneficial for women
with a mid-range recurrence score of 11 to 25.

10. PlanB: Design
R
TC x 6
EC-D x 8
• Female 18-75
• HER2-
• pT1-4
• pN+
• pN0 + 1
risk factor
• >2cm
• G2-3
• HR-
• Age <35
• uPA/PAI-1 ↑
• Initiated in 2009 as randomised comparison of EC-D (8 cycles) versus TC (6
cycles)

11. PlanB: Design
O
N
C
O
T
Y
P
E
D
X
HR-
HR+
>4 LNs
or 0-
3LNs +
RS>11
0-3 LNs
and RS<11
R
TC x 6
EC-D x 8
Endocrine
therapy
• Female 18-75
• HER2-
• pT1-4
• pN+
• pN0 + 1
risk factor
• >2cm
• G2-3
• HR-
• Age <35
• uPA/PAI-1 ↑
• Early amendment in 2009 to recommend no chemo in patients with RS <11
• Pre-planned exploratory DFS analysis by RS at 3 and 5 years
• RS result known to participants

12. PlanB: Choice of cutoff
RS 11 = 10% risk of
distant recurrence
(assuming upper limitof
95%CI)
Paik S et al. N Engl J Med 2004;351:2817-2826.

13. PlanB: Demographics
characteristic N=2642
Age, median, yrs 56
T size, median,
mm
19
Nodal Status
pN0
pN1
pN2
pN3
1554 (58.8)
930 (35.2)
122 (4.6)
36 (1.4)
Grade (local)
G1
G2
G3
Unknown
165 (6.2)
1629 (61.7)
526 (19.9)
322 (12.2)
RS available and HR+ and post-amendment and pN0-1
n=2274
RS 0-
11
n=404
(17.8%)
RS 12-
25
n=1397
(61.4%)
RS >25
n=473
(20.8%)
ET only: n=348
(86.1%)
CT:n=1078
(78.6%)
CT: n=409
(89.7%)
CT n = 50
Dropout n=6
Gluz et al. JCO 2016; 34:2341
 April 2009 – December 2011 3198 from 93 German centres
Demographics (locally HR+)

14. PlanB: 3-year DFS
RS 3-year DFS
>25 91.9% (89.0 - 94.8)
12-25 97.8% (96.8 - 98.8)
0-11 97.4% (95.6 - 99.1)
DFS events:
54 distant relapses
11 secondary neoplasms (mainly contralateral BC) / local recurrence
8 Deaths without relapse
P < .001
Gluz et al. JCO 2016; 34:2341

15. PlanB: 3-year DFS
pN0 to 1 BC; treated with no
chemotherapy if RS ≤ 11 and
treated by chemotherapy if RS ≥
12
RS 3-year DFS (95% CI)
>25 94.9% (91.4 - 98.4)
12-25 97.5% (95.9 - 99.0)
0-11 98.4% (97.0 - 99.8)
P < .05
Gluz et al. JCO 2016; 34:2341

16. PlanB: 5-year DFS
Gluz et al. ASCO 2016 abstract556
RS 5-year DFS
>25 84%
12-25 94%
0-11 94% (pN0, pN1)
P < .001
pN0 to 1 BC; treated with no
chemotherapy if RS ≤ 11 and
treated by chemotherapy if RS ≥
12

17. TAILORx: Design
O
N
C
O
T
Y
P
E
D
X
• Female 18-75
• ER and / or PR +ve
• HER2-ve
• 1.1 – 5.0 cm
and any grade
• 0.6-1.0 cm
and grade 2/3
• Node-negative
• Unblinded, RS result known to participants

18. TAILORx: Design
O
N
C
O
T
Y
P
E
D
X
RS >25
ETRS 0-10
CT+ET
• Female 18-75
• ER and / or PR +ve
• HER2-ve
• 1.1 – 5.0 cm
and any grade
• 0.6-1.0 cm
and grade 2/3
• Node-negative

19. TAILORx: Design
O
N
C
O
T
Y
P
E
D
X
RS >25
R
ET
• primary endpoint – IDFS
• sample size based on non-inferiority of ET versus CT+ET in the 11-25 RS
population
RS 11-25
RS 0-10
ET
CT+ET
CT+ET
• Female 18-75
• ER and / or PR +ve
• HER2-ve
• 1.1 – 5.0 cm
and any grade
• 0.6-1.0 cm
and grade 2/3
• Node-negative

20. TAILORx: Design
O
N
C
O
T
Y
P
E
D
X
RS >25
R
ET
• March 2015: interim data monitoring committee recommended results of the
low risk group be released
• results of the primary comparison are awaited (?? SABCS 2017)
RS 11-25
RS 0-10
ET
CT+ET
CT+ET
• Female 18-75
• ER and / or PR +ve
• HER2-ve
• 1.1 – 5.0 cm
and any grade
• 0.6-1.0 cm
and grade 2/3
• Node-negative

21. TAILORx: Demographics
• from April 2006 – Oct 2010 10 273 eligible pts recruited at 1,000
sites (USA, Australia, Canada, Ireland, New Zealand, Peru)
Characteristic RS 0-10
(n=1629)
RS 11-25
(n=6897)
P
value
Age, median
(IQR) -yrs
58 (50-64) 55 (48-62) <0.001
T size, median
(IQR) - cm
1.5 (1.2-2.0) 1.5 (1.2-2.0) 0.31
Grade
• G1
• G2
• G3
(n=1578)
530 (34%)
937 (59%)
111 (7%)
(n=6665)
1941 (29%)
3812 (57%)
912 (14%)
<0.001
PR
• Negative
• Positive
(n=1590)
28 (2%)
1562 (98%)
(n=6752)
528 (8%)
6224 (92%)
<0.001
O
N
C
O
T
Y
P
E
D
X
RS >25
ET
• AI 59%
• Tam 34%
• Tam-AI 1%
• OS 3%
RS 11-25
RS 0-10 1629 / 15.9%
6897 / 67.3%
1736 / 16.9%
CT 6 pts
Sparano et al. N Engl J Med2015;373:2005-2014

22. TAILORx: RS 0-10 Outcomes at 5yrs
Sparano et al. N Engl J Med2015;373:2005-2014
93.8% (95%CI92.4-94.9) 99.3% (95%CI98.7-99.6)
98.7% (95%CI97.9-99.2) 98.0% (95%CI97.1-98.6)
IDFS events
• local / regional recurrence – 8
• distant recurrence – 10
• contralateral primary - 15
• other new primary cancer - 43
• death - 12

25. What do PlanB and TAILORx tellus?
 Possible to identify a population with very good prognosis with ET alone
 PlanB: patients with RS 0-11: DFS is 94%
 TAILORx: patients with RS 0-10: iDFS is 93.8% and risk of distant recurrence
at 5 years <1%
 No scope for meaningful chemotherapybenefit
 Do these studies provide evidence of clinical utility?
 benefit over clinico-pathological decision making is not addressed
 many of these patients at low clinical risk and would not be offered
chemotherapy in the UK
 outcomes better than predicted – selected population (RS known)
 low risk group is a minority of patients (15.9% TAILORx, 17.8% PlanB)

26. In this trial, among 6711 women with hormone-receptor–
positive, HER2-negative, axillary node–negative breast
cancer and a midrange recurrence score of 11 to 25 on the
21-gene assay, endocrine therapy was not inferior to
chemoendocrine therapy, which provides evidence that
adjuvant chemotherapy was not beneficial in these patients.

27. • The 9-year rate of distant recurrence in women with a
recurrence score of 11 to 25 in our trial was
approximately 5%, irrespective of chemotherapy use,
• Updated results for patients with a low recurrence score
of 10 or less, who were previously reported as having a
1% distant recurrence rate at 5 years in our trial,now
indicate a 9-year rate of distant recurrence of
approximately 3%.

28. Although the rate of nonadherence to the
assigned treatment was 12% overall, the
sample size was adjusted to compensate for
this, and the as-treated analysis produced
results similar to those of the intention-to-treat
analysis.

29. • A total of 40% of women who were 50 years of age or younger had
a recurrence score of 15 or lower, which was associated with a low
rate of recurrence with endocrine therapy alone.
• Exploratory analyses indicated that chemotherapy was associated
with some benefit for women 50 years of age or younger who had a
recurrence score of 16 to 25 (a range of scores that was found in
46% of women in this age group).

30. A greater treatment effect from adjuvant chemotherapy has
been noted in younger women, which may be at least partly
explained by an antiestrogenic effect associated with
premature menopause induced by chemotherapy

31. ASCO guidelines recommend that the use of the assay be
considered in cases of hormone-receptor– positive, HER2-
negative breast cancer and high clinical risk but not low
clinical risk as defined in that trial
73 % low and 27 % high

33. MINDACT: CONSORT

34. MINDACT: Design
A
D
J
U
V
A
N
T
high C / high G
R
ET
• Female 18-70
• Any ER / PR /
HER2
• T1-T3
• N0 / N1 *
• *N0 until Aug2009
low C / low G
ET
CT+ET
CT+ET
M
A
M
M
A
P
R
I
N
T
high C / low G
low C / high G
Clinical risk (C) (Adjuvant!)
• low C risk: 10yr
BCSS>88% in ER+ve,
>92% in ER-ve
Genomic Risk (G): 70 gene signature
• binary

35. MINDACT: Design
A
D
J
U
V
A
N
T
• Female 18-70
• Any ER / PR /
HER2
• T1-T3
• N0 / N1 *
M
A
M
M
A
P
R
I
N
T
R
ET
CT+ET
high C / low G
high C / high G
ETlow C / low G
CT+ET
low C / high G
• *N0 until Aug 2009
• primary endpoint – DMFS at 5 years
• primary hypothesis: lower boundary for 95%CI would be > 92% in high C / low
G treated with ET alone
• risk allocations are unblinded

36. MINDACT: Patient Enrollment
• from 2007 – 2011 11 288 eligible pts screened and 6693 enrolled at
112 European sites
In 275 pts C or G risk was corrected later during the trial:
(1) Mammaprint analytical validity compromised May 2009- Jan2010
(2) Incorrect clinical data from site (size, grade, nodes, receptors)
Cardoso F et al. N Engl J Med2016;375:717-729
low C / low G
n=2745
(41%)
low C / high
G n=592
(8.8%)
high C / low G
n=1550 (23.2%)
high C / high
G n=1806
(27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET
screened
n=11 288
tissue sample unsuitable for mammaprint
(26%)
pt / investigator decision (20%)

37. MINDACT: concordant groups
Characteristic high C / high G
age (median) 53
T size >2cm 48%
Node-positive 26%
Grade 3 76%
subtype
• luminal
• triple neg
• Her2
50%
31%
19%
low C / low G
n=2745
(41%)
low C / high
G n=592
(8.8%)
high C / low G
n=1550
(23.2%)
high C / high G
n=1806 (27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET
96% chemo

38. MINDACT: concordant groups
Characteristic high C / high G
age (median) 53
T size >2cm 48%
Node-positive 26%
Grade 3 76%
subtype
• luminal
• triple neg
• Her2
50%
31%
19%
low C / low G
n=2745
(41%)
low C / high
G n=592
(8.8%)
high C / low G
n=1550
(23.2%)
high C / high G
n=1806 (27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET
Characteristic low C / lowG
age (median) 55
T size <2cm 96%
Node-negative 94%
Grade 1 or 2 98%
subtype
• luminal
• Her2
96%
4%
96% chemo
99%
no chemo

39. MINDACT: disconcordant groups
Characteristic high C / low G
age (median) 55
T size >2cm 58%
Node-positive 48%
Grade 3 29%
subtype
• luminal
• Her2
• triple neg
90%
9%
1%
low C / low G
n=2745
(41%)
low C / high
G n=592
(8.8%)
high C / low G
n=1550
(23.2%)
high C / high G
n=1806 (27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET
85% chemo
adherence
89% no chemo

40. MINDACT: disconcordant groups
Characteristic low C / high G
age (median) 55
T size <2cm 98%
Node-negative 97%
Grade 1 or 2 85%
subtype
• luminal
• Her2
• triple neg
79%
12%
9%
low C / low G
n=2745
(41%)
low C / high
G n=592
(8.8%)
high C / low G
n=1550
(23.2%)
high C / high G
n=1806 (27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET 80% chemo
adherence
88% no chemo
Characteristic high C / low G
age (median) 55
T size >2cm 58%
Node-positive 48%
Grade 3 29%
subtype
• luminal
• Her2
• triple neg
90%
9%
1%
85% chemo
89% no chemo

41. MINDACT: primary outcome
• 5yr DMFS in high CP / low G group who did not receiveadjuvant
chemotherapy
• “primary test population" n=644; (excludes change in risk n=21, received
chemo 85)
5yr DMFS rate = 94.7%
(95%CI 92.5 - 96.2)
Cardoso F et al. N Engl J Med2016;375:717-729
low C / low G
n=2745 (41%)
low C / high G
n=592 (8.8%)
high C / low G
n=1550 (23.2%)
high C / high G
n=1806 (27%)
enrolled
n=6693
R
ET
CT+ET
R
ET
CT+ET
Mammaprint identifies women with
sufficiently good prognosis with ET
alone that chemo unlikely to offer
meaningful benefit

42. MINDACT: different populations

43. MINDACT: secondary analyses
• 5yr DMFS in discordant groups randomised to chemotherapy versus nochemotherapy;
ITT population
Cardoso F et al. N Engl J Med2016;375:717-729
Treatment strategy N % DMFS at 5 yrs HR p-value
High C,
Low G
Follow C risk / CT 749 95.9 (94.0-97.2) 0.78 (0.5-1.21) 0.267
Follow G risk / No CT 748 94.4 (92.3, 95.9) 1.00 -
Low C,
High G
Follow G risk / CT 344 95.8 (92.9-97.6) 1.17 (0.59 – 2.28) 0.657
Follow C risk / No CT 346 95.0 (91.8, 97.0) 1.00 -
1.5% difference

44. MINDACT: DMFS in 4 risk groups
(corrected risk, ITT)
Cardoso F et al. N Engl J Med2016;375:717-729
% at 5yrs
Low C / Low G 97.6
Low C / High G 94.8
High C / Low G 95.1
High C / High G 90.6

45. MINDACT: nodal status
• exploratory analysis: 5yr DMFS in C-high C, G-low risk group randomised to
chemotherapy versus no chemotherapy; intention-to-treat population
Cardoso F et al. N Engl J Med2016;375:717-729

46. What does MINDACT tell us?
 patients with high clinical risk and low genomic risk may consider
omission of chemotherapy (level 1A evidence) based on good
prognosis
 5yr DMFS rate = 94.7% (95%CI 92.5 - 96.2)
 absolute detriment 1.5% DMFS, 2.8% DFS, 1.4% OS in ITT (per
protocol results very similar)
 not significant (except DFS) but study not powered to assess statistical
significance of these differences
 patients with low clinical risk and high genomic risk did not appear
to fare better with addition of chemotherapy

47. What does MINDACT tell us?
 every study has its problems!
 analytical validity compromised: concerning for the clinician
 incorrect clinical data (but only ~1.5%)
 assay could not be performed in 10% of screened patients
 Inclusion of patients with TNBC (9.6%) and HER2+ve (9.5%)
 Is there evidence of clinical utility?
 no apparent benefit in ”upstaging” low C risk patients to
receive chemo
 based on the study population chemo could be avoided in
46% of high risk patients (1550 / 3356)

48. CONCLUSION
The results of trial suggest that the 21-gene assay may
identify up to 85% of women with early breast cancer who
can be spared adjuvant chemotherapy, especially those who
are older than 50 years of age and have a recurrence score
of 25 or lower, as well as women 50 years of age or younger
with a recurrence score of 15 or lower.

49. Ongoing clinical trials are obtaining additional information
on the clinical usefulness of the 21-gene assay in women
with hormone-receptor–positive breast cancer and positive
axillary nodes and evaluating the clinical usefulness of the
50-gene assay in this context.

50. Where does OPTIMA fit in thislandscape?
• OPTIMA “tests using the test”
• randomisation is to use the test or not
• use of the test is (partially) blinded
• ensures participants are sufficiently high clinical risk to warrant
chemotherapy
endocrine
Option 1
(control)
1
R
1
Option 2
(research)
treatment
assignedbyrisk
chemo. endocrine
chemo. endocrine
blinded to randomisation
1° Outcome = Non-inferiority of IDFS(∆=-3%)
Cost effectiveness evaluation of test-directed treatment
Prosigna
high risk
ROR ≥61
ROR<61
low risk
R
ET (n=2000)
CT+ET (n=2000)• N1
• ER and / or PR+ve
• HER2-ve
• RS<25
OPTIMA RxPONDER

52. RxPONDER (in progress)
R
ET (n=2000)
CT+ET (n=2000)• N1
• ER and / or PR +ve
• HER2-ve
• RS<25
stratification factors:
• RS (0-13 vs. 14-25)
• menopausal status
• axillary surgery
• tests whether chemotherapy benefit depends on recurrence score (interaction of RS and
chemotherapy benefit tested in a Cox regression model ofDFS)
• If the interaction is statistically significant and there is a point of equivalence betweenthe
two randomized treatments for some RS value in the range 0-25, a clinical cutpoint for
recommending chemotherapy will be estimated
• RS result known to participants
• results ?2020

53. Thank you