Breast cancer: Molecular STAGING classification and testing. Korourian A : AP,CP ; MD,PHD(Molecular medicine)

Breast cancer: Molecular STAGING classification and testing Korourian A : AP,CP ; MD,PHD(Molecular medicine)

Breast Cancer Theory: Halsted Operative breast cancer is a local-regional disease The positive lymph node is the source of distant metastases

Breast Cancer Theory: Spectrum Operative breast cancer is a systemic disease in many but not all cases Positive lymph node is correlated with the subsequent appearance of distant metastases

How does breast cancer staging (TNM) influence prognosis? Tumor Size (pt) Nodal Stage (pn) TNM Staging TNM staging is used to help determine prognosis and risk of recurrence Staging affect s choice of therapy and treatment planning pt and pn reflect the patients tumor burden which is independently associate with prognosis T1 = < 2 cm T2 = 2.1 5 cm T3 = > 5 cm T4 = skin/chest wall invasion N0 = no lymph node involvement N1 = 1 3 positive nodes N2 = 4-9 positive nodes N3 = > 10 positive nodes Cancer 1989;63:181 187 Cancer 1983;52:1551 1557

How does histologic grade influence prognosis? HG1 HG2 HG3 Modified SBR Grade 3-5: Grade I - Well 6-7: Grade II - Moderate 8-9: Grade III Poor Significantly correlates with DFS & OS Histopathology. 1991;19(5):403-410, J Clin Pathol. 2002 Feb;55(2):88-92, J Clin Oncol. 2007;25(10):1239-46

Molecular Portrait of Breast Cancers Basallike HER-2 Norma l Luminal B Luminal A Sorlie T et al, PNAS 2001 Slide courtesy of L. Carey

Is molecular/biological profiling the future of breast cancer diagnosis? The answer is YES! The role of molecular profiling in clinical practice is still evolving. What is the most practical, relevant, cost-effective, & broadly applicable ancillary testing that can help determine prognosis? o Can this approach be reliably used to guide the selection of beneficial treatment regimens? Can target therapy be done? o Can some patients be spared the cost and morbidity of treatments that will be ineffective? The Pathology community has an opportunity to correlate molecular results and help inform treatment planning.

Are traditional approaches to making decisions about adjuvant treatment still useful? Decisions on systemic adjuvant therapy based on risk assessment: o Weigh background level - risk of recurrence against benefits & burdens of adjuvant therapy o Patient factors (clinically validated) Age, menopausal status and co-morbidities o Tumor-related factors (clinically validated) Tumor size (tumor burden), grade, LN, LVI Factors are robust prognostic markers, weaker in predicting for Rx response

How does breast cancer staging (TNM) influence prognosis? Tumor Size (pt) Nodal Stage (pn) TNM Staging TNM staging is used to help determine prognosis and risk of recurrence Staging affect s choice of therapy and treatment planning pt and pn reflect the patients tumor burden which is independently associate with prognosis T1 = < 2 cm N0 = no lymph node involvement T2 = 2.1 5 cm N1 = 1 3 positive nodes T3 = > 5 cm N2 = 4-9 positive nodes T4 = skin/chest wall invasion N3 = > 10 positive nodes Cancer 1989;63:181 187 Cancer 1983;52:1551 1557

How does histologic grade influence prognosis? HG1 HG2 HG3 Modified SBR Grade 3-5: Grade I - Well 6-7: Grade II - Moderate 8-9: Grade III Poor Significantly correlates with DFS & OS Histopathology. 1991;19(5):403-410, J Clin Pathol. 2002 Feb;55(2):88-92, J Clin Oncol. 2007;25(10):1239-46

Which ER(+)/HER2(-) breast cancer patients are the most likely to benefit from chemotherapy? (St. Gallen's) Relative indication for chemotherapy Factors not useful for decision* Relative indication for endocrine therapy alone Pathologic Features ER & PR Low expression of ER & PR (or ER[+]/PR[-]) High expression of ER & PR Histologic grade Grade 3 Grade 2 Grade 1 Proliferation High (Ki-67 >20%) Borderline (10-20%) Low (Ki-67 <10%) Nodal status Positive (4 or more) Positive (1-3 nodes) Negative LVI Presence (especially extensive) +/- Absence Tumor size (pt) > 5 cm 2.1 5 cm < 1-2 cm *Validated multigene assays may be an adjunct to high-quality pathologic phenotyping if doubt about the indications for chemotherapy persist after consideration of all pathologic factors Multigene assay* High risk score Intermediate Low risk score Goldhirsch Annals of Oncology, 20:1319-1329(2009)

What are the different ways we can look at breast cancer to understand prognosis? Features Low Grade Disease High Grade Disease Histologic Grade (Morphology) DNA copy # changes (CGH Pattern) +1q/-16q/simple changes recurrent amplifications, and deletions RNA expression (Gene Expression Profiling) Clinical Significance Indolent clinical course Aggressive clinical course

How does histologic grade correlate with gene expression? G1 G2 G3 G1 G3 Low GGI = Low Risk Recurrence High GGI = High Risk Recurrence Histologic grade significantly correlates with prognosis G1 and G3 tumor show different gene expression profiles These profiles (genomic grade index) are associates with: - Low risk for recurrence (G1) - High risk for recurrence (G3) J Clin Oncol. 2007;25(10):1239-46, Sotiriou, C. et al. J. Natl. Cancer Inst. 2006 98:262-272

How do pathologic features correlate with molecular classification? Cheng, JNCI 2009. ER+ HER2- Ki67 <14% Luminal A ER+ ER+ HER2- Ki67>14% Luminal B Breast Cancer HER2+ ER+ HER2+ Luminal HER2 ER- ER- HER2+ ER/PR/HER2- CK5/6 +/- EGFR HER2 Enriched Basal-Like Prognostic Significance ER- PR- HER2- TNBC Non-Basal Perou, Sorlie et al. 2001, 2003.

What factors are helpful to predict for chemotherapy sensitivity/benefit in breast cancer? Factors in favor of selecting adjuvant chemotherapy Clinical/Pathologic features ER negative Ductal histology Grade 3 High proliferation Tumor biology/molecular Basal-like (chemo) and HER2 positive (chemo + HER2 targeted therapy) High risk MammaPrint, Oncotype DX or PAM50 Factors against selecting adjuvant chemotherapy Clinical/Pathologic features ER positive (high expression) Lobular histology (classic) Grade 1 Low proliferation Tumor biology/molecular Luminal A type Low risk MammaPrint, Oncotype DX or PAM50 Nat Rev Clin Oncol, 8;272-279(2011)

What approaches have been used to classify breast cancer based on gene expression data? Molecular Classification Gene-Expression Prognostic Signatures,21,50,70 gene Recurrence score Luminal A Luminal B HER2+ Basal-Like Genes associated with tumor differentiation & cell cycle drive the prognostic power of the intrinsic molecular classification and several gene expression signatures Array,PCR based Genomic grade Quantitative measurement of proliferation and differentiation genes Well differentiated/low proliferation Poorly differentiated/high proliferation Sotiriou et al. NEJM 2009;360:790-800. Low Grade Good Prognosis High Grade Poor Prognosis

Proliferation genes are a common driving force in prognostic signatures. Tumors with high proliferation are more aggressive and have a better chemo response. What intrinsic properties of breast cancer are most important for understanding clinical course? Intrinsic Biologic Properties of Breast Tumor 70 gene signature 50 gene signature Genomic Grade Index High Tumor Proliferation Aggressive Clinical Course Poor Prognosis More Responsive to Chemo 21 gene recurrence score Intrinsic Molecular Classification

What criteria are currently used to predict benefit from systemic adjuvant therapies? Type of Therapy Endocrine therapy Criterion Any ER staining by IHC (>1% ER+ invasive tumor)* Anti-HER2 therapy Chemotherapy HER2 positive by IHC: circumferential membrane staining that is complete and intense, observed in a homogeneous and contiguous population and within >10% of the invasive tumor cells*. By ISH: HER2/CEP17 2.0* HER2+ disease = Chemo + HER2-targeted therapy Triple negative (ER-, PR- and HER2-) = Chemo ER+/HER2 negative = variable indication for Chemo, based on biology + risk Treatment thresholds are based on disease biology, tumor characteristics and estimated risk for recurrence. *ASCO-CAP Guidelines

What elements are reported on breast cancer at <insert your organization s name>? Reporting Elements Histologic grade Clinical Significance Correlates with clinical course and potential benefit from systemic therapy Tumor Size LVI Nodal Status HER2 ER/PR Proliferation Margin status Multigene assays Measurement of tumor burden, correlates with prognosis and likelihood of recurrence Correlates with lymph node mets, local and distant recurrence Measurement of tumor burden, correlates with prognosis and likelihood of distant recurrence Correlates with aggressive disease and benefit from chemo and targetedtherapy Correlates with benefit from endocrine therapy Correlates with clinical course and benefit from systemic therapy (most useful for ER+) Correlates with likelihood of local recurrence Correlates with prognosis and potentially systemic treatments benefit

Which is True? Prosigna,Pam50 (FFPE) and MammaPrint (frozen tissue) are FDA cleared tests, Oncotype (FFPE) is not. ALL have been clinically validated in several different studies and work WELL All breast cancer molecular tests must be performed in a CLIA certified laboratory. CLIA has no standards for breast cancer molecular testing, nor does it provide proficiency testing. Oncotype (FFPE) can be done in IRAN, it is sent abroad.

HER-2 Chromosome 17,about 20% tumor are positive, dual color or mono color test Some test like Ventana are FDA approved,but in iran done by non- FDA approved tests. ASCO- CAP guide line for scoring Eqap program abroad but not in iran Use for target therapy FISH, SISH, CISH, PCR based method. CISH is a good reliable method, done by expert pathologist

HER-2 cish testing

Hereditary breast cancer

Thank you : Any question?