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1、In Pursuit of Personalized Therapy for Breast Cancer: Gene Expression Signatures,Jane S. Chawla, M.D.November 6, 2009,Objectives,Case: Chemotherapy or NOTWho should receive adjuvant chemotherapy?The birth of gene-expression signatures: Intrinsic breast cancer subtypesGene Expression Signatures under
2、 development70-gene Signature21-gene Signature2-gene Signature50-gene signatureCase revisited,Should the patient receive chemotherapy?,Clinical Case,30 y/o WF with newly diagnosed IDC R breastMMG / Ultrasound 1.2 x 1.2 cm mass at 10 oclock + surrounding microcalcifications + several suspicious axill
3、ary LNss/p bilateral mastectomies at OSHSurgical Path - 4.6 cm lesion consisting of IDC mixed with DCIS; intermediate grade; + lymphovascular invasion; 11 (-) LNs; ER+/PR+/HER-2-; T2N0M0Oncotype DX - - low risk for recurrenceBased on oncotype results her oncologist recommended adjuvant tamoxifen x 5
4、 yearsPt presents for a second opinion,How else can we differentiate these tumors?,Who Should Receive Adjuvant Chemotherapy?,65% of women with invasive breast cancer have LN(-) diseaseAdjuvant chemotherapy improves DFS and OS in pre- and postmenopausal women 70 with LN+/- breast cancerNSABP B-14 & B
5、-20 showed the benefit of tamoxifen & chemo in ER+/LN- breast cancerLikelihood of distant mets at 10 years is about 15%85% of pts are overtreated if chemo given to all patientsThose with poor prognostic features benefit most from chemotherapyMain clinical prognostic factors: age, tumor size, axillar
6、y LN status, tumor histology, grade, and hormone-receptor status,Sotiriou, C. et al. NEJM, 2009.,Luminal A,Luminal B,HER2+,Basal-like,Intrinsic Breast CancerSubtypes described byPerou et al.,Express amountsOf luminal cyto-Keratins & geneticMarkers of luminalEpithelial cells ofNormal tissue,Express l
7、evels of EGFR, c-kit, & growth factors like hepatocyte growth factor and IGF,Gene Expression Profiles or “Signatures”,Composed of a selection of genes felt to provide prognostic or predictive information about tumorsA number of gene expression signatures have been developed to help identify those pa
8、tients at highest risk for recurrent diseaseThis may avoid chemotherapy administration to patients at low risk,The 70-gene Assay: MammaPrint,Mammaprint: Development of the 70-Gene Signature,DNA microarray analysis of 78 breast primary tumors (untreated)Pts were 55 years of age with T1-2/N0 diseasePt
9、s selected based on outcome: Distant metastases within 5 yearsStatistical analysis, “supervised classification,” identified 231 genes correlated with disease outcome Top 70 genes selectedGenes that regulate cell cycle, invasion, metastasis, & angiogenesisPatients categorized as “good prognosis” or “
10、poor prognosis.”Found to be a better predictor of distant metastases within 5 years than all clinical variables in this studyOdds ratio (distant metastases): poor to good prognosis groups = 15,Van t Veer, L. Nature, 2002.,Retrospective Validation of the 70-Gene Signature,295 women ages 52 with T1-2,
11、 LN-/+ breast cancer226 ER+ / 69 ER-chemo 31%; hormonal 7%; both 7%61 pts included in the analysis were used to develop 70-gene signature,Van de Vijver. NEJM, 2002.,Prognosis Signature Predictive of End Points (10 years),995% 2.6%,555% 4.4%,85 % 4.3%,51 % 4.5%,Probability of RemainingMetastasis-free
12、,Overall Survival,Multivariate Analysis,Independent predictors of risk of distant metastasis as a 1st event,70-gene signatureTumor diameterChemotherapy,Lymph node statusVascular invasion,Authors report that gene signature is predictive of distant mets in LN+ pts,Multivariate analysis argues that LN
13、status isindependent of gene signature as a predictor,Van de Vijver. NEJM, 2002.,TRANSBIG Independent Retrospective Validation Study,Retrospective evaluation of 302 pts from several sites in Europe (age60, T1-2, LN-) previously untreatedAim: to examine whether the 70-gene signature had prognostic va
14、lue independent of the best clinical risk classifications (St Gallens, Nottingham Prognostic Index, & adjuvant online),Buyse, M. J of NCI, 2006.,Does 70-gene Signature have Independent Prognostic Value?,Gene signature adds independent prognostic information to that provided by various risk classific
15、ationsThe signature remained a statistically significant prognostic factor for time to distant metastases & OS even after adjustment for various risk classifications (HR 2.15 & 2.15, respectively),Buyse, M. J of NCI, 2006.,Forrest Plot of HR for Time to Distant Metastases,Although, average HR of 2.3
16、2 is significantthere was wide variation in the HRs among clinical sites.Therefore model is very sensitive to variation in patient population,ClinicalSites,Buyse, M. J of NCI, 2006.,Conclusions of Validation Studies,Studies were retrospectiveConcern for overfitting with supervised analysis of relatively small sample sizes and large numbers of genesThe first validation study contained 61 patients from study on which the classifier was builtClaims exceed evidence?,
