Molecular Profiling in Breast Cancer: Are Traditional Grading and Staging Obsolete?

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1 Molecular Profiling in Breast Cancer: Are Traditional Grading and Staging Obsolete? Thomas J. Lawton MD Director, Seattle Breast Pathology Consultants Seattle, WA

2 Traditional Staging (TNM) T: Tumor size N: Nodal status M: Metastasis

3 Other Prognostic/Predictive Factors Patient age Tumor grade ER/PR positivity HER2/neu over-expression

4 These factors are all taken into consideration in determining prognosis and whether a patient will benefit from chemotherapy

5 Do our standard grading and staging effectively predict prognosis and who will benefit from chemotherapy?

6 Factors used in staging and prediction/prognosis Patient age Tumor size Tumor grade Lymph node status ER/PR positivity HER2 over-expression Metastasis

7 Factors used in staging and prediction/prognosis Patient age Tumor size Tumor grade Lymph node status ER/PR positivity HER2 over-expression Metastasis

8 Traditional Histologic Grading Invasive carcinomas are divided into three grades using the Bloom-Richardson (Nottingham) scheme: Grade I or well-differentiated Grade II or moderately-differentiated Grade III or poorly-differentiated

9 Bloom-Richardson (Nottingham) Grading Scheme The overall grade is based upon a cumulative score of each of the three features of the invasive carcinoma: Tubule formation (1-3) Nuclear pleomorphism (1-3) Mitotic activity (1-3) Grade I tumors: overall score 3-5 Grade II tumors: overall score 6-7 Grade III tumors: overall score 8-9

10 Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups. Rakha EA et. al. JCO 26(19): , 2008

11 Rakha EA et. al. JCO 26(19): , 2008

12 For 612 operable patients, two laboratory characteristics, the number of histologically positive nodes and the histologic grade, were the most valuable predictors. These two factors alone form a predictive index that may be an excellent and simple guide for the clinical decision of subsequent therapy. Contesso G, et. al. JCO 5: , 1987

13 For 398 patients with inoperable breast cancer (ie, tumor greater than or equal to 7 cm, N2-3, inflammatory, skin fixation, and clinically rapidly growing forms), the histologic grade (performed on drill or cutting needle biopsy) was again a most important (and with inflammatory forms the most important) predictor of prognosis in these patients. Contesso G, et. al. JCO 5: , 1987

14 How reproducible is histologic grading in breast cancer?

15 Dalton LW, et. al. Cancer 73: , pathologists 10 tumors Complete agreement on grade in 3 cases >78% agreement on grade in 6 cases

16 Delides GS et. al. Arch Pathol Lab Med 106(3): , pathologists 158 tumors Agreement in only 23 cases! Best agreement in grade I and grade III

17 Longacre T, et. al. Mod Pathol 19(2): , pathologists 35 tumors Agreement (means): Grade I Grade II Grade III Disagreement usually in grade II tumors

18 Why do pathologists have difficulty in agreeing on Histologic grade?

19 Tubule Formation

20 Nuclear Pleomorphism

21 Mitotic Activity

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23 Factors used in staging and prediction/prognosis Patient age Tumor size Tumor grade Lymph node status ER/PR positivity HER2 over-expression Metastasis

24 Reproducibility of ER Reporting 300 labs surveyed 8 different antibodies used Wide variations in antibody dilutions Wide variations in scoring results 8% used computer assisted image analysis Follow-up study of 3 institutions evaluating 35 cases had 26% disagreement rate for positive result Layfield LF, et. al. Breast J 6:189-96, 2006

25 Reproducibility of HER2 Testing Approximately 20% of current HER2 testing may be inaccurate. ASCO/CAP guidelines: IHC: 30% of tumor with uniform intense staining. FISH: negative < 1.8, positive >2.2. Wolff AC, et. al. JCO 131(1): 18-43, 2007.

26 Adjuvant! Online Developed in 2001 Based upon SEER data and results of individualized trials Computerized model that takes clinicopathologic features and provides clinicians with prognostic information and the risk/benefits of chemotherapy

27 Adjuvant! Online Shown to accurately predict 10-year mortality rate. Ravdin, et. al. JCO 19: , 2001 and Olivotto, et. al. JCO 23: , 2005 Also predictive of degree of benefit from chemotherapy Unpublished data, reported in Paik C, et. al. Arch Path Lab Med 133(6): ,

28 Problems with Current Grading and Staging Inter-observer variability in grading of carcinomas. Inter-observer and inter-laboratory variability in immunhistochemical testing for ER/PR and HER2/neu. Algorithms are based upon population cohorts and not necessarily predictive in a specific patient.

29 The Impact of Inter-Observer Variation in Pathological Assessment of Node-Negative Breast Caner on Clinical Risk Assessment and Patient Selection for Adjuvant Systemic Treatment. 694 patients <61 years old T1-T4/N0/M0 28% discordance between local and central review for tumor grade Assignment to different risk group in 15% and 8% using Dutch guidelines or Adjuvant! Online, respectively. Bueno-de-Mesquita JM, et. al. Ann Oncol (epub ahead of print)

30 Examples for the audience: Would you recommend chemotherapy for this patient given this pathology and clinical history?

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32 Nearly all respondents agreed no chemotherapy for this patient

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34 Nearly all respondents said yes to chemotherapy for this patient

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36 As expected, a very mixed response for this patient

37 Molecular Profiling of Breast Cancer Luminal A Luminal B HER2 over-expressing Basal-like Normal breast Sorlie T, et. al. PNAS 100(14): , 2003.

38 Molecular Profiling of Breast Cancer Luminal A Luminal B HER2 over-expressing Basal-like Normal breast

39 The basal subtype was repeatedly recognized as a distinct group in each of the three independent data sets, and should be considered as a separate disease with respect to treatment and follow up. Sorlie T, et. al. PNAS 100(14): , 2003.

40 OncotypeDX TM 21 gene assay Can be performed on FFPE tissue Node-negative, ER-positive patients Has prognostic ability as well as predictive of degree of benefit from systemic chemotherapy Provides recurrence score broken into three categories: low, intermediate, high risk

41 OncotypeDX TM Low risk: RS<18 Intermediate risk: RS High risk: 31 or > Low risk patients have significantly better prognosis (Paik S, et. al. NEEJM 351: , 2004) Compared to NCCN or St. Galen guidelines, OncotypeDX placed 50% of patients into the low risk group with similar 10-year distant disease-free survival compared to 10% in the B-14 trial (Unpublished data, reported in Paik S, et. al. Arch Path Lab Med 133(6): , 2009)

42 TAILORx trial Intermediate risk group expanded to RS of Patients in this group will be randomized to endocrine therapy alone or endocrine therapy + chemotherapy Data won t be available for at least 4-5 years

43 MammaPrint R 70 genes Requires fresh tissue Has prognostic capabilities No definite proven predictive capabilities as of yet Places patients into only low and high risk groups

44 MammaPrint R 123 patients, <55 years Stage: T1-2N0 Assay was compared to four commonly-used clinico-pathologic risk indices In multivariate analysis, it out-performed the four clinico-pathologic risk indices and was a strong independent prognostic factor. Bueno-de-Mesquita JM, et. al. Breast Cancer Res Treat 117(3): , 2009

45 MINDACT Trial Hoping to enroll 6000 lymph node negative patients Risk will be assessed by Adjuvant! Online and MammaPrint R If discordant risk, patients will be randomized to follow results of one of the tests

46 Are traditional grading and staging of breast cancer obsolete? Do we still need to perform ER/PR and HER2/neu?

47 Triple-Negative Cancers Are Not All Basal-Like Two large cohorts of breast cancer cases Triple negative cancers vs. basal-like cancers Basal markers: CK 5/6, CK 14, CK 17, EGFR Basal-like cancers vs. triple-negative only cancers were positively associated with BRCA1 mutations, a unique pattern of distant metastases, a better response to systemic chemotherapy, but shorter survival. Rakha EA, et. al. Clin Cancer Res 15(7): , 2009

48 Immunohistochemistry for Basal-Like Carcinomas 611 breast cancer samples Expression of basal keratins 17 and/or 5/6 associated with poor clinical outcome In multivariate analysis, in node-negative patients, expression of these keratins was a prognostic marker independent of tumor size and grade van de Rijn M, et. al. A J Pathol 161(6): , 2002

49 IHC-Based Assays ProEx TM Br (TriPath Oncology, NC) 5 antibodies Uses image analysis Over-expression of 2 or more markers is associated with disease relapse in nodenegative and node-positive patients No definite prediction of response to chemotherapy Whitehead CM, et. al. Mod Pathol 17:50A, 2004

50 IHC-Based Assays Mammostrat R (Applied Genomics, AL) 5 antibodies ER-positive, node-negative tumors In multivariate analysis, risk of recurrence was independent of stage, grade, and LN status Ring BZ, et. al. JCO 24: , 2006

51 What is in our future?

52 Improved breast cancer prognosis through the combination of clinical and genetic markers A hybrid signature was developed combining clinico-pathologic factors and the 70-gene assay The hybrid signature performed better than the 70-gene assay alone, clinical markers alone, or the St. Galen consensus criteria The odds ratio for developing distant metastasis for patients with a good vs. bad prognosis using the hybrid signature was far better than using genetic or clinical markers alone Sun Y, et. al. Bioinformatics 23(1): 30-37, 2007