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Can we use multigene-tests to guide
the adjuvant treatment of early breast
J Natl Compr Canc Netw 2013;11:174-182 J
R5 陳三奇
VS 趙大中
• Breast cancer
– A heterogeneous disease
– Outcome predict by clinical and pathologic
– Genomic tests since 2002
• Oncotype DX, PAM50, and MammaPrint.
• Others: Rotterdam 76-gene signature, 3-gene
– The role of these multigene tests ?
NSABP B-14 、B-20 trial
10 years follow up
• Early breast cancer with ER(+) and LN (-)
• NSABP B-14 trial (National Surgical Adjuvant Breast and Bowel
Project clinical trial B-14. )
– Randomly assigned to placebo (n=1453) or tamoxifen (n=1439)
– Recurrent free survival :hazard ratio 0·58 (95% CI 0·50–0·67,
– Overall survival: HR 0·80, (95% CI 0·71–0·91, p=0·0008)
• NSABP B-20 trial
– Randomly assigned to tamoxifen (n=788) or cyclophosphamide,
methotrexate, fluorouracil, and tamoxifen (CMFT, n=789)
– Rcurrence-free survival 0·52 ( 0·39–0·68,p<0·0001)
– Overall survival 0·78, (0·60–1·01, p=0·063)
Fisher et al. Lancet 2004; 364: 858–68
Fisher et al. Lancet 2004; 364: 858–68
Fisher et al. Lancet 2004; 364: 858–68
• Conclusions of NSABP B-14 and B-20 trial 10 years follow up:
– 1. Tamoxifen has much benefit in ER(+) and LN (-) patients.
– 2. Older women tend to have higher tumor oestrogen-receptor
concentrations and are more likely to benefit from tamoxifen than
from chemotherapy; in younger women, the converse is true
Fisher et al. Lancet 2004; 364: 858–68
Oncotype DX
• Oncotype DX score:
– Quantitative reverse transcriptase polymerase chain
reaction (RT-PCR)
– measures 21 genes in formalin-fixed paraffinembedded breast tumors.
Oncotype DX to Predict Recurrence of
Tamoxifen-Treated, Node-Negative Breast Cancer
• Retrospective analysis of 668
tumor blocks in NSABP –B14
– ER (+), LN (-), Tamoxifentreated
Low v.s. high-risk groups
(6.8% vs. 30.5; P<.001)
Paik et al. N Engl J Med 2004;351:2817-26
• Conclusion of Oncotype DX for NSABP B-14 trial:
– The RS quantified the likelihood of distant recurrence in
tamoxifen-treated patients with ER(+), LN(-) breast cancer.
Paik et al. N Engl J Med 2004;351:2817-26
Oncotype DX to Predict Death of
Node-Negative Breast Cancer
• A case-control study
– N= 4969
– Node-negative, EBC from 1985 to 1994, not treated with adjuvant
– 220 patients died from breast cancer.
• Treated with tamoxifen, the death rate was
– Low risk: 2.8 %
– Intermediate risk: 10.7%
– High risk :15% (P=.003).
• Not treated with Tamoxifen for ER(+) patients, the death rate was
– Low risk: 6.2%.
– Intermediate risk: 17.8%
– High risk :19.9%
• Conclusion:
– The RS strongly associated with risk of breast cancer death among ERpositive, tamoxifen-treated and untreated patients.
Habel et al. Breast Cancer Research 2006, 8:25
• The 21-gene recurrence score (RS) assay
– quantifies the likelihood of distant recurrence in women with
• ER (+), LN (-), treated with adjuvant Tamoxifen.
– Strongly related to cancer death in
• ER (+), LN (-), treated with or without Tamoxifen.
• Suggest that
– combining Recurrence Score, tumor grade, and tumor size
provides better risk classification than any one of these factors
• However, the relationship between the RS and
chemotherapy benefit is not known.
Oncotype DX to Predict Recurrence of
Tamo or CMF-treated,LN(-), ER (+) Breast Cancer
Low risk
Int. risk
• Retrospective
analysis of the RS in
– NSABP B-20
– LN (-), ER (+),
– Treated with
tamoxifen or
Tamoxifen plus
High risk
Paik et al. J Clin Oncol 2006,24:3726-3734.
• Conclusions:
– High risk patients experienced a significant benefit
from chemotherapy , whereas low risk patients had no
Paik et al. J Clin Oncol 2006,24:3726-3734.
Oncotype DX to Predict DFS and OS of
postmenopausal , ER(+), LN(+) treated with CT
• SWOG-8814, INT-0100
– Postmenopausal women, ER (+), LN (+)
– Randomized into 3 group for adjuvant therapy :
• Tamoxifen
(cyclophosphamide, doxorubicin, and fluorouracil x 6 cycles,
Tamoxifen for 5 years)
• Results:
– CAF-T or CAFT was superior to Tamoxifen for DFS, and
marginally for OS.
– Adjusted HRs favoured CAF-T over CAFT.
KS el tl.Lancet. 2009 Dec 19;374(9707):2055-63
Oncotype DX to Predict DFS and OS of
postmenopausal , ER(+), LN(+) treated with CT
Tamoxifen alone
•Retrospective analysis the recurrence score on DFS by treatment group
(tamoxifen vs CAF-T)
N= 367 specimens, tamoxifen, n=148; CAF-T, n=219.
Albain et al. Lancet Oncol 2010; 11: 55–65
All patients
Low risk group
Int. risk group
High risk group
Disease free survival
Albain et al. Lancet Oncol 2010; 11: 55–65
Low risk group
Int. risk group
– High RS, LN (+), ER(+) benefit from
addition of CAF to Tamoxifen in free
survival (HR, 0.59; log rank P=.033)
with the addition of CAF
– Low RS did not benefit from
adjuvant chemotherapy, despite positive
High risk group
Overall survival
Albain et al. Lancet Oncol 2010; 11: 55–65
• The use of Oncotype DX may identify
– LN(-), ER (+) EBC with high risk of recurrence.
– LN(+), ER (+) EBC with low risk of recurrence may
not have benefit from chemotherapy.
NCCN guideline
• TAILORx trial:
– 11,000 patients with ER+, HER2–, node-negative breast cancer.
– RS: Arm A: <11, B/C: 11-25 , D:>25
– Trial enrollment completed in 2010 and trial results are not yet
• RxPONDER trial (SWOG S1007) January 2011
– ER+, HER2– breast cancer with 1 to 3 positive nodes (N1)
– Enroll 4000 women with an RS of 25 or less, 2000 patients per
arm planned
– The primary
• effect of chemotherapy on LN(+) breast cancer who have an RS of 25
or less.
– Secondary objectives
• comparison of Oncotype DX and PAM50 risk of relapse (ROR) scores
Prospective Clinical Trials of Oncotype
PAM50 ROR score
PAM50 ROR score
• Use RT-qPCT to categorizes tumors into the 4 intrinsic
luminal A
luminal B
• ROR score to estimate the probability of relapse at 5
Parker el al. J Clin Oncol 27:1160-1167
Tamoxifen-treated, earlystage, ER+ breast cancer,
DSS= disease specific
Samuel Leung et al. Clin cancer research 2010;16:5222
IHC status
• NCIC MA12 trial
– Predict the benefit of tamoxifen in premenopausal women in the,
whereas ER status alone had limited value.
Dongsheng Tu et al.Clin Cancer Res 2012;18:4465-4472.
• TransATAC analysis
– Good agreement between PAM50 ROR and Oncotype
– PAM50 ROR score provided more prognostic
information about 10-year distant recurrence than
Oncotype DX
– More patients assigned to the low-risk category by
• half of the patients in the intermediate-risk Oncotype DX
group were classified into the low-risk PAM50 luminal A
• RxPONDER trial
Dowsett et al 2011 Cancer research
MammaPrint and the MINDACT
Prospective Clinical Trial
• Using DNA microarrays, a 70-gene
prognostic signature, MammaPrint, for nodenegative breast cancer was developed in 2002.
(2002 Nature)
– low- or high-risk for distant metastases at 5 years.
– MammaPrint outperformed standard clinical and
histologic predictors of patient prognosis.
– approved by the FDA in 2007 for node-negative
• The MINDACT trial
(Microarray In Node-negative and 1–3 Node-Positive Disease May Avoid Chemo Therapy)
– Prospective randomized phase III clinical trial
– MINDACT had a predefined pilot phase in which
the data and treatment decisions of the first 800
patients were analyzed, and those results were
published in 2011. (2011 Eur J Can)
The MINDACT trial
• Chemotherapy:
– anthracycline-containing regimen
– or docetaxel/capecitabine.
• Endocrine therapy:
– a switching strategy of tamoxifen for 2 years, then letrozole for 5
years, versus
– letrozole for 7 years
• Question 1: Should we use gene-predictors to
define the need of adjuvant treatment?
• MammaPrint
– prognosis in untreated node-negative patients.
– 29% discordance in low and high risk groups
between Adjuvant! and MammaPrint
• 32% low risk with Adjuvant!
– => high risk with MammaPrint
• 68% high risk with Adjuvant!
– => low risk with MammaPrint
– The MINDACT will address this issue
• Question 2: Should we use gene predictors to guide
treatment choice, particularly to understand if an ERpositive tumor needs chemotherapy in addition to hormone
• NCCN suggest
– Chemotherapy in case of node positivity
– Oncotype DX :negative nodes with T>1 cm
• St. Gallen suggest
– favor chemotherapy if a tumor is >5 cm or if 4+ metastatic nodes.
• If a tumor is between 2 and 5 cm, or if only 1-3 nodes
– Oncotype DX
• High recurrent score: predict chemotherapy benefit
• Low recurrent score: no evidence of benefit.
• Gray zone in intermediate RS
– RS: 11- 25, 45% of all subjects
– Ongoing TAILORx trial
• Question 3: Can we use genomic predictors to
choose the type of chemotherapy?
• A multigene signature predictive of the activity
of paclitaxel and 5-fluorouracil, doxorubicin,
and cyclophosphamide (FAC), in neoadjuvant
– Complete pathological response : more powerful
predictor of treatment outcome.
– multigene signature
• positive predictive value is modest (52%)
• negative predictive value is high (92%)
• We can probably select what not to use, but not
what to use
Ayers M el al. J Clin Oncol 2004;22(12):2284
• Question 4: Are genomic predictors ready for
routine clinical practice?
• Combining one or more gene-expression
classifiers into a single model together with
traditional clinico-pathological parameters
hat still retain important prognostic
Future Developments:
Cancer Genome Sequencing
• A revolution in DNA sequencing technology
began in 2005.
• 2009–2010 ,Washington University School of
• Sequenced the patient’s normal DNA, the primary
tumor DNA, and the DNA of the metastasis
– identified somatic DNA changes.
– significant evolution in the cancer can occur during
metastatic spread
Luminal subtype breast cancers, a statistically significant difference (P=.02) is
seen in the number of point mutations
Point mutation
black: copy number
green: interchromosome translocation
blue: intra-chromosome
• Similarly, comparison of the genomes of basal-like, HER2enriched, luminal A, and luminal B breast cancers, as
defined by PAM50, shows that the number of
translocations is much higher in basal-like and HER2enriched cases. (2012 nature)
• The neoadjuvant AI trial, ACOSOG Z1031, were sequenced
– TP53
• higher preoperative endocrine prognostic index scores
• higher pretreatment and posttreatment proliferation indexes.
• mutations in the transcription factor
• associated with response to AI therapy.
– MAP3K1
• low pre– and post–AI treatment Ki-67 level (the opposite of p53)
• correlated with good-prognosis breast cancer.
• Genome sequencing
– may identify the molecular abnormalities
– identified poor risk by multigene tests
– provide potential new targets for therapy
Thanks for your attention~