current
trial
TAILORx: Trial Assigning Individualized
Options for Treatment (Rx)
Joseph A. Sparano
Clinical Breast Cancer, Vol. 7, No. 4, 347-350, 2006
Key words: Oncotype DX™ assay, Recurrence Score, REMARK Guidelines
Introduction
Approximately 125,000 women in North America were
diagnosed with estrogen receptor (ER)–positive breast can-
cer associated with negative axillary lymph nodes in 2005.1
Treatment guidelines recommend adjuvant chemotherapy
for all women whose tumor size exceeds 1 cm or women
with smaller tumors associated with unfavorable histologic
features.2 By these criteria, adjuvant chemotherapy could
be recommended for as many as 75,000 women aged < 70
years annually in the United States. Currently, it is esti-
mated that approximately 25% of all women with early-stage
ER-positive breast cancer receive adjuvant chemotherapy,
or approximately 32,000 annually, and its use has increased
substantially over the past 15 years.3 Chemotherapy is used
in approximately 75% of those aged < 50 years, 30% between
the ages of 50 years and 69 years, and approximately 5% in
those * 70 years.
Adjuvant Chemotherapy for
Early-Stage Estrogen Receptor–Positive
Breast Cancer
Approximately 85% of women with early-stage ER-posi-
tive breast cancer are adequately treated with adjuvant
hormonal therapy. Although adding chemotherapy reduces
the risk of recurrence on average by approximately 25%, the
absolute benefit for an individual patient is small, ranging
from 1% to 5%.4 The vast majority of patients with ER-
positive breast cancer are therefore overtreated with chemo-
therapy, because most would have been cured with hormonal
therapy alone. Until recently, there have been no predictive
factors that could identify individuals more likely to benefit
from chemotherapy. Therefore, treatment recommendations
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY
Submitted: Jun 12, 2006; Revised: Aug 30, 2006 Accepted: Sep 25, 2006
Address for correspondence: Joseph A. Sparano, MD, Albert Einstein
College of Medicine, Breast Evaluation Center, Montefiore-Einstein
Cancer Center, Bronx, NY 10461
Fax: 718-904-2892; e-mail: jsparano@montefiore.org
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have generally been based upon prognostic factors, with che-
motherapy recommended if the residual risk of recurrence
exceeded approximately 5%-10% despite adjuvant hormonal
therapy.2 Decision aids such as Adjuvant Online,5 decision
boards,6 and other tools are often useful to assist patients
and caregivers with information regarding absolute benefits
that might be expected from chemotherapy.7 Although such
decision aids might assist some patients in making a more
informed decision regarding whether to accept adjuvant
chemotherapy when faced with a choice, many patients and
their clinicians err on the side of overtreatment because of
the imprecise nature of predicting treatment benefit.8
Trial Assigning Individualized Options
for Treatment (Rx)
TAILORx (Trial Assigning Individualized Options for
Treatment [Rx]) is the first trial that has been developed as
a result of the National Cancer Institute’s Program for the
Assessment of Clinical Cancer Tests (PACCT; www.cancer-
diagnosis.nci.nih.gov/assessment/index.html). The purpose
of this program is to integrate the most modern diagnostic
tests into clinical decision-making in order to individual-
ize cancer treatments. Because TAILORx is the first trial
to be developed as a result of the PACCT initiative, it
has also been referred to as PACCT-1. The PACCT initia-
tive has also led to the REMARK Guidelines (Reporting
Recommendations for Tumor Marker Prognostic Studies).9
One of the major objectives of TAILORx is to reduce chemo-
therapy overtreatment by integrating molecular diagnostic
testing into the clinical decision-making process. The trial
is available through the Cancer Trials Support Unit
(www.ctsu.org) and is being coordinated by the Eastern
Cooperative Oncology Group. Other participants include
the National Surgical Adjuvant Breast and Bowel Project
(NSABP) and all members of the North American Breast
Intergroup, including the Southwest Oncology Group,
Cancer and Leukemia Group B, North Central Cancer
Treatment Group, National Cancer Institute of Canada,
and the American College of Surgeons Oncology Group.
Clinical Breast Cancer October 2006 • 347
TAILORx

Table 1 21 Genes Used for the Recurrence Score Assay Figure 1 Validation Study of Oncotype DX™: Tamoxifen-Treated
(16 Cancer and 5 Reference Genes) Patients from NSABP B-14 (N = 668)

RS Genes Mutiplication RS Genes Mutiplication A 100

Factor Factor
HER2 Invasion 80

Distant Recurrence-Free
Grb7 Stromelysin 3

Survival (%)
+0.47 +0.1 60
HER2 Cathepsin L2
Estrogen CD68 +0.05
40
ER GSTM1 –0.08
PR BAG-1 –0.07 20 Low Risk (RS <18) n = 338
–0.34 Intermediate Risk (RS 18-30) n = 149
Bcl-2 Reference High Risk (RS • 31) n = 181
Genes
Scube2 0 2 4 6 8 10 12 14 16
Proliferation `-actin Years
Ki-67 GAPDH
STK15
B Low-Risk Group Intermediate-
Risk Group
High-Risk Group
RPLPO 1 40
Survivin +1.04
GUS 35
Cyclin B1
30

Distance Recurrence
MYBL2 TFRC

at 10 Years (%)
25
Recurrence Score Risk Stratification
20
Category RS (0-100) 15
Low risk < 18
10
Intermediate risk • 18 and < 31
5
High risk • 31
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Rationale for Choosing the Oncotype
DX™ Assay Figure 2 TAILORx Schema
A number of molecular diagnostic tests and prognostic
molecular signatures have been evaluated, including several Preregistration
tests that are commercially available.10 The Oncotype DX™
molecular diagnostic test is being used in TAILORx for sev- Oncotype DX™ Assay
eral important reasons. It is a 21-gene reverse-transcriptase
polymerase chain reaction–based assay that may be performed Register
on routinely processed, formalin-fixed, paraffin-embedded tis- Specimen Banking
sue. The assay includes 16 tumor genes and 5 reference genes,
with the result expressed as a computed recurrence score (RS;
Table 1).11 The genes used in the assay were identified in sev- Secondary Primary Secondary
Study Group 1 Study Group Study Group 2
eral training set trials, followed by a validation study that was RS <11 RS 11-25 RS > 25
performed in patients with ER-positive, node-negative breast ~29% of ~44% of ~27% of
cancer who received a 5-year course of tamoxifen in NSABP Population Population Population
trial B-14. Higher RS was associated with an increased risk of
distant recurrence, whether evaluated as a dichotomous vari- Arm A Randomize Arm D
able or a continuous variable (Figure 1). A subsequent popula- Hormonal Stratification Factors: Chemotherapy
Therapy Alone Tumor Size, plus
tion-based validation study performed in patients treated in the Menopausal Status, Hormonal
Kaiser-Permanente healthcare system provided further valida- Planned Chemotherapy, Therapy
tion for the robustness of the assay.12 In addition, subsequent Planned Radiation
studies in patients treated with tamoxifen with or without
adjuvant chemotherapy in NSABP trial B20 indicated that
Arm B Arm C
only patients with an increased RS derived benefit from adju- Hormonal Therapy Chemotherapy plus
vant chemotherapy.13 Although it is clear that patients with Alone Hormonal Therapy
a very low RS do very well with hormonal therapy alone, and

348 • Clinical Breast Cancer October 2006

 Joseph A. Sparano

Table 2 Recurrence Score and Response to Chemotherapy in NSABP B-20 Trial by Recurrence Score (N = 651)11
Number of Tamoxifen Tamoxifen plus HR (95% CI) for
RS Chemotherapy Recurrence by Addition P Value
Patients (%) 10-Year DDFS (%)
10-Year DDFS (%) of Chemotherapy
< 11 177 (27) 98 95 1.788 (0.36-8.868) 0.471
11-25 279 (43) 95 94 0.755 (0.313-1.824) 0.531
> 25 195 (30) 63 88 0.285 (0.148-0.551) < 0.0001

Chemotherapy included cyclophosphamide, methotrexate, 5-fluorouracil, or methotrexate/5-fluorouracil.

Abbreviations: CI = confidence interval; DDFS = distant disease-free survival; DFS = disease-free survival; HR = hazard ratio

patients with a very high RS benefit from chemotherapy, there
is still uncertainty as to whether chemotherapy is necessary for
patients who have a mid-range RS and who meet established
clinical criteria for adjuvant chemotherapy.
Trial Design
After informed consent and preregistration, a tumor
specimen is forwarded to Genomic Health for the Oncotype
DX™ assay, with a result reported to the site within 10-14
days. After the Oncotype DX™ RS is known, patients are
registered and have their treatment assigned or randomized
based upon the RS (Figure 2):
• If the RS is ) 10: hormonal therapy alone.
• If the RS is * 26: chemotherapy plus hormonal therapy.
• If the RS is 11-25: patients will be randomized to receive
chemotherapy plus hormonal therapy (the standard
treatment arm) versus hormonal therapy alone (the
experimental treatment arm).
The choice of the hormonal therapy regimen and che-
motherapy regimen will be at the discretion of the treating
physician but must be consistent with one of several stan-
dard options described in the protocol document. Patients
can also enroll on other Cancer Trials Support Unit trials
as long as the protocol treatment is consistent with the
TAILORx-assigned treatment arm (ie, hormonal therapy or
chemotherapy plus hormonal therapy). In addition, patients
who have already had the Oncotype DX™ assay performed
are eligible to enroll if their RS is 11-25. At the time of regis-
tration and treatment assignment, patients will be asked to
provide blood samples for banking of plasma and peripheral
blood mononuclear cells. Tissue specimens will be collected
undertreatment in the high-risk group (also called “secondary
study group 2”) and the randomized group (also called the “pri-
mary study group”). When the NSABP B20 data were analyzed
using the RS ranges used in TAILORx, the treatment effect
of chemotherapy was similar to the original analysis (Table
2). Although a trend favoring the addition of chemotherapy
becomes evident at an RS of approximately 11 when the risk
of relapse is analyzed in a linear fashion, the 95% confidence
intervals completely overlap in the 11-25 RS range (Figure 3).
Finally, high RS has also been associated with an increased risk
of local relapse, which might also be reduced by giving adjuvant
chemotherapy.14 An RS of 11 is associated with a risk of local
and distant relapse of approximately 10%, a threshold that has
been typically used for recommending adjuvant chemotherapy.
Conclusion
TAILORx represents a major step forward into the era
of personalized medicine for breast cancer. By integrating
a molecular diagnostic test into clinical decision-making,
patients and clinicians will be able to make more informed
decisions regarding the most appropriate treatment options.
This trial will also serve as an important resource for evalu-
ating new molecular signatures and other technologies, such
as proteomics, epigenomics, and pharmacogenomics, as
technologies evolve.
Figure 3 Rationale for Primary Study Group RS Range of 11-25
Based upon NSABP B-20 Results (Linear Fit with 95% CI)
40
Tamoxifen
Tamoxifen plus Chemotherapy

by the Eastern Cooperative Oncology Group Pathology 30

Distance Recurrence

Coordinating Office, with central testing and confirmation

at 10 Years (%)

Benefit
of ER and progesterone receptor expression, creation of tis- from
20 Chemotherapy
sue microarrays, and RNA extraction for future studies.

10
Rationale for the Recurrence Score
Ranges in TAILORx
The RS ranges used in TAILORx are different than those
0 10 20 30 40 50
originally described for the low- (< 18), intermediate- (18-
Recurrence Score
30), and high-risk (> 30) groups as originally reported for the
assay. The range was adjusted to minimize the potential for Abbreviation: CI = confidence interval

Clinical Breast Cancer October 2006 • 349

TAILORx
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