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Can we use multigene -tests to guide the adjuvant treatment of early breast cancer?. R5 陳三奇 VS 趙大中 . J Natl Compr Canc Netw 2013;11:174-182 J. Breast cancer A heterogeneous disease Outcome predict by clinical and pathologic features. Genomic tests since 2002

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can we use multigene tests to guide the adjuvant treatment of early breast cancer

Can we use multigene-tests to guide the adjuvant treatment of early breast cancer?

R5 陳三奇

VS 趙大中

J NatlComprCancNetw 2013;11:174-182 J

slide2

Breast cancer

    • Aheterogeneous disease
    • Outcome predict by clinical and pathologic features.
    • Genomic tests since 2002
      • Oncotype DX, PAM50, and MammaPrint.
      • Others: Rotterdam 76-gene signature, 3-gene SCMGENE panel
    • The role of these multigene tests ?
nsabp b 14 b 20 trial 10 years follow up
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, p<0·0001)
    • 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

slide4

NSABP B-14

NSABP B-20

Fisher et al. Lancet 2004; 364: 858–68

slide5

CMFT

Tamo

Placebo

Fisher et al. Lancet 2004; 364: 858–68

slide6

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

Placebo

Tamo

CMFT

Fisher et al. Lancet 2004; 364: 858–68

oncotype dx
Oncotype DX
  • Oncotype DX score:
    • Quantitative reverse transcriptase polymerase chain reaction (RT-PCR)
    • measures 21 genes in formalin-fixed paraffin-embedded breast tumors.
oncotype dx to predict recurrence of tamoxifen treated node negative breast cancer
Oncotype DX to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer
  • Retrospective analysis of 668 tumor blocks in NSABP –B14 trial
    • ER (+), LN (-), Tamoxifen-treated

Low v.s. high-risk groups (6.8% vs. 30.5; P<.001)

Paik et al. N Engl J Med 2004;351:2817-26

slide9

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
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 chemotherapy.
    • 220 patients died from breast cancer.
  • Treated with tamoxifen, the death ratewas
    • 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 ER-positive, tamoxifen-treated and untreated patients.

Habel et al. Breast Cancer Research 2006, 8:25

slide11

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 alone.
  • 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
Oncotype DX to Predict Recurrence of Tamo or CMF-treated,LN(-), ER (+) Breast Cancer
  • Retrospective analysis of the RS in
    • NSABP B-20
    • LN (-), ER (+),
    • Treated with tamoxifen or Tamoxifen plus chemotherapy (CMF-T)

Low risk

Int. risk

High risk

Paik et al. J ClinOncol 2006,24:3726-3734.

slide13

Conclusions:

    • High risk patients experienced a significant benefit from chemotherapy , whereas low risk patients had no benefit.

Paik et al. J ClinOncol 2006,24:3726-3734.

oncotype dx to predict dfs and os of postmenopausal er ln treated with ct
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
      • CAF-T (cyclophosphamide, doxorubicin, and fluorouracil x 6 cycles, Tamoxifenfor 5 years)
      • CAFT
  • Results:
    • CAF-T or CAFT was superior to Tamoxifenfor DFS, and marginally for OS.
    • Adjusted HRs favoured CAF-T over CAFT.

KS el tl.Lancet. 2009 Dec 19;374(9707):2055-63

slide15

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(tamoxifenvsCAF-T)
    • N= 367 specimens, tamoxifen, n=148; CAF-T, n=219.

Albain et al. Lancet Oncol 2010; 11: 55–65

slide16

Low risk group

All patients

Int. risk group

High risk group

Disease free survival

Albain et al. Lancet Oncol 2010; 11: 55–65

slide17

Conclusion:

    • 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 node.

Low risk group

High risk group

Int. risk group

Overall survival

Albain et al. Lancet Oncol 2010; 11: 55–65

slide18

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

slide19

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 available.
  • 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
pam50 ror score1
PAM50 ROR score
  • Use RT-qPCT to categorizes tumors into the 4 intrinsic subtypes
    • luminal A
    • luminal B
    • HER2-enriched
    • basal-like
  • ROR score to estimate the probability of relapse at 5 years.

Parker el al. J ClinOncol 27:1160-1167

slide23

Tamoxifen-treated, early-stage, ER+ breast cancer,

DSS= disease specific survival

Samuel Leung et al. Clincancer research 2010;16:5222

slide24

IHC status

  • NCIC MA12 trial
    • Predict the benefit of tamoxifen in premenopausal women in the, whereas ER status alone had limited value.

PAM50

DongshengTuet al.Clin Cancer Res 2012;18:4465-4472.

slide25

TransATAC analysis

    • Good agreement between PAM50 ROR and Oncotype DX
    • PAM50 ROR score provided more prognostic information about 10-year distant recurrence than Oncotype DX
    • More patients assigned to the low-risk category by PAM50.
      • half of the patients in the intermediate-risk Oncotype DX group were classified into the low-risk PAM50 luminal A category.
  • RxPONDERtrial

Dowsett et al 2011 Cancer research

mammaprint
MammaPrint
  • Using DNA microarrays, a 70-gene prognostic signature, MammaPrint, for node-negative breast cancer was developed in 2002. (2002 Nature)
    • low- or high-risk for distant metastases at 5 years.
    • MammaPrintoutperformed standard clinical and histologicpredictors of patient prognosis.
    • approved by the FDA in 2007 for node-negativepatients.
slide28

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)
slide31

Chemotherapy:

    • anthracycline-containing regimen
    • or docetaxel/capecitabine.
  • Endocrine therapy:
    • a switching strategy of tamoxifen for 2 years, then letrozole for 5 years, versus
    • letrozolefor 7 years
slide34

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
slide35

Question 2: Should we use gene predictors to guide treatment choice, particularly to understand if an ER-positive tumorneeds chemotherapy in addition to hormone therapy?

slide36

NCCN suggest

    • Chemotherapy in case of node positivity
    • OncotypeDX :negative nodes with T>1 cm
  • St. Gallensuggest
    • 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 positive?
    • OncotypeDX
      • 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
slide38

A multigene signature predictive of the activity of paclitaxel and 5-fluorouracil, doxorubicin, and cyclophosphamide(FAC), in neoadjuvant setting

    • 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

slide40

Combining one or more gene-expression classifiers into a single model together with traditional clinico-pathological parameters hat still retain important prognostic information.

future developments cancer genome sequencing
Future Developments: Cancer Genome Sequencing
  • A revolution in DNA sequencing technology began in 2005.
  • 2009–2010 ,Washington University School of medicine.
  • 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
slide42

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
slide43

Similarly, comparison of the genomes of basal-like, HER2-enriched, luminal A, and luminal B breast cancers, as defined by PAM50, shows that the number of translocations is much higher in basal-like and HER2-enriched cases. (2012 nature)

slide44

The neoadjuvant AI trial, ACOSOG Z1031, were sequenced

    • TP53
      • higher preoperative endocrine prognostic index scores
      • higher pretreatment and posttreatmentproliferation indexes.
    • GATA3
      • 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 multigenetests
    • provide potential new targets for therapy