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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 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?

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  1. 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

  2. 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 ?

  3. 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

  4. NSABP B-14 NSABP B-20 Fisher et al. Lancet 2004; 364: 858–68

  5. CMFT Tamo Placebo Fisher et al. Lancet 2004; 364: 858–68

  6. 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

  7. Oncotype DX • Oncotype DX score: • Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) • measures 21 genes in formalin-fixed paraffin-embedded breast tumors.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. Low risk group All patients Int. risk group High risk group Disease free survival Albain et al. Lancet Oncol 2010; 11: 55–65

  17. 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

  18. 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

  19. 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

  20. Prospective Clinical Trials of OncotypeDX:TAILORx and RxPONDER

  21. PAM50 ROR score

  22. 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

  23. Tamoxifen-treated, early-stage, ER+ breast cancer, DSS= disease specific survival Samuel Leung et al. Clincancer research 2010;16:5222

  24. 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.

  25. 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

  26. MammaPrint and the MINDACT Prospective Clinical Trial

  27. 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.

  28. 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)

  29. The MINDACT trial

  30. http://www.lifemath.net/cancer/breastcancer/therapy/

  31. 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

  32. Question 1: Should we use gene-predictors to define the need of adjuvant treatment?

  33. 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

  34. 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?

  35. 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

  36. Question 3: Can we use genomic predictors to choose the type of chemotherapy?

  37. 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

  38. Question 4: Are genomic predictors ready for routine clinical practice?

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

  40. 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

  41. 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

  42. 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)

  43. 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

  44. Thanks for your attention~

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