Classification of Breast Cancer & Update on Triple-Negative Breast Cancer

Transcription

1 Classification of Breast Cancer & Update on Triple-Negative Breast Cancer W. Fraser Symmans, M.D. Department of Pathology UT M.D. Anderson Cancer Center

2 HER2 Proliferation Estrogen Dependence DIFFERENTIATION Progenitor cell Signal transduction Cell survival DNA Repair Cell survival Signal transduction Cell cycle control Cell cycle control Chemotherapies Endocrine Therapies

3 Gene Expression Profiles Might Augment Pathology Images courtesy of Affymetrix, Inc.

4 Molecular Classification Of Breast Cancer Basal c-erbb-2 Normal breast Luminal epithelial ER-positive Unsupervised Hierarchical Clustering (500 Intrinsic Genes) - Cell Types Perou et al. Nature 2000;406:747-52

5 Pathwork Tissue of Origin Example Report Test not cleared by the FDA for sale in the U.S. For Investigational Use Only

6 M485 M120 M287 M464 M230 M407BW07 M310 M576 M111 M302 M186 M239 M126 M159 M499 M627 M130 M215 M406 M444 M235 M382 M402 M121 M439 M580 M617 M332 M503 M113 M205 M605 M594 M443 M611 M154 M628 M321 M136 M636 M608 M255 M146 M282 M497 M193BW02 M442 M458 M180 M418 M304 M145 M141 M251 M403BW06 M399 M108 M220 M139 M466 M228 M194 M386 M238 M569 M434 M266 M384 M469 M421 M506 M385 M181 M536 M107 M575 M176 M523 M270 M231 M155 M117 M322 M366 M165 M157 M341 M565 M419 M246 M257 M196 M128 M508 M264 M201 M Threshold of 500 is shown Threshold of 500 is shown Threshold of 500 is shown 0 0 ESR1 M399 M314 M153 M228 M521 M234 M611 M636 M310 M226 M553 M434 M211 M580 M603 M497 M373 M227 M485 M139 M463 M111 M341 M129 M207 M473 M196 M385 M286 M180 M458 M313 M158 M246 M231 M523 M337 M270 M128 M357 M375 M366 M534 M256 M620 M201 M628 M442 M141 M245 M605 M567 M145 M371 M186 M199 M594 M251 M382 M194 M316 M418 M258 M235 M239 PERU11 PERU31 US154 US181 US071 PERU29 US141 US173 US100 US084 GM14 US088 US016 US032 GM16 US164 US127 US054 US142 US024 US128 US074 US166 US148 US111 US089 US090 US047 US182 US026 US060 US059 US067 US115 GM11 US168 US104 PERU17-19 US158 ML44 US108 ML54 PERU09 US117 US080 US149 US151 US093 US085 US186 US087 US163 US134 US144 PERU07 PERU28 PERU02 US014 US049 PERU06 US096 PERU01 B38 FA37 B05 B13 FA09 FA01 FA14 B10 FA13 jox0588 B26 B17 jox0890 FA39 B28 jox1168 B35 B24 jox1177 B16 jox0928 B29 B11 jox2002 jox0876 jox0706 jox0779 jox0511 B32 jox1525 B15 jox1982 jox1097 FA43 jox1331 jox1579 B40 FA50 jox0055 jox0837 jox0742 B14 jox0676 jox2027 jox2069 jox1181 B08 jox0427 jox1167 jox1766 jox0209 B22 jox1103 jox0192 jox1432 jox0114 jox1889 jox4904 B30 jox0595 jox1107 jox1125 jox1804 jox0555 jox1127 jox2175 jox1397 jox1156 jox0550 jox1769 jox1981 jox0596 jox0638 jox2341 jox0738 B12 ESR1 ESR Single Gene Measurements of ER and HER2 are Accurate N = 193 N = 123 N = 151 N = N = 104 N = Threshold of 1150 is shown Threshold of 1150 is shown Threshold of 1150 is shown 0 0 ERBB2 B02 B40 B10 B13 B33 B41 B31 B30 B38 B35 B26 B32 B15 B07 B01 B06 B29 B08 B19 B28 B16 B25 B42 B24 B36 B11 B37 B23 B18 B27 B22 B04 B09 B03 B17 B14 B39 B05 US118 GM11 GM03 ML20 US080 US082 US019 US154 ML70 US057 US067 US110 US111 US071 PERU31 US135 US112 US160 PERU01 US165 US032 US107 US011 GM05 US033 PERU12-14 ML44 PERU02 PERU16-18 PERU05 US151 US038 PERU09 US085 US084 US149 US182 US148 GM14 US137 US102 US179 US145 PERU17-19 US169 US101 PERU10 US020 US016 PERU15-17 US180 US170 ERBB2 ERBB2 FNA FNA Tissue Gong et al. Lancet Oncol 2007;8:203-11

7 HER2 Status By mrna Expression (Affymetrix Gene Profiles) Updated Results Using ASCO/CAP Guidelines HER2 Status ERBB2 (n = 393) IHC (n = 252) FISH (n = 329) IHC &/or FISH (n = 393) Area under ROC curve Agreement with mrna cutoff at % 93% 94% HER2 Status (IHC &/or FISH) ERBB2 mrna Status Negative Negative 70% Positive 3% Positive 6% 21%

8 Predicting Endocrine Sensitivity Estrogen Dependence ER-negative ER-positive Symmans, et al. ASCO 2005 Abstr 546 Symmans, et al. SABCS 2005 Abstr 308 Symmans, et al. SABCS 2006 Abstr 1027

9 Evaluation of Endocrine Sensitivity Index in Patients with ER+ Metastatic Breast Cancer (LAB ) FNA Of ER+ MBC Total of 323 patients eligible for hormonal Rx 239 second-line, 84 first-line Endocrine Therapy Chemotherapy AI Receptor Modulator Affymetrix U133A Gene Array (Endocrine Sensitivity Index) Compare Treatment Groups TTP ORR

10 Diminution of ER Genomic Signature With Advancing Stage of Disease (n = 351) SET Index GAPDH I IIA IIB III IV STAGE I IIA IIB III IV STAGE Symmans et al. SABCS 2006 #1027

11 HER2 Proliferation Estrogen Dependence DIFFERENTIATION Progenitor cell Signal transduction Cell survival DNA Repair Cell survival Signal transduction Cell cycle control Cell cycle control Chemotherapies Endocrine Therapies

12 Triple Negative Breast Cancer Basic Features High grade Highly aggressive phenotype CK 5/6 and 17 positive P-cadherin postive

13 Breast Cancer Subtypes, Race and Age N Basal- like HER2+ (ER-) Luminal A Luminal B Premenopausal African-American American 97 39% 9% 36% 9% Postmenopausal African- American 99 14% 7% 59% 16% Premenopausal non African-American American % 6% 51% 18% Postmenopausal non African-American American % 6% 58% 16% TOTAL % 7% 51% 16% P= Carey LA et al, JAMA 2006

14 Treatment Choices in Triple-Negative Breast Cancer Chemotherapy Chemotherapy Chemotherapy Bevacizumab

15 ECOG 2100 Bevacizumab added to weekly paclitaxel in first line MBC R A N D O M I Z E Paclitaxel + Bevacizumab Paclitaxel 28-day cycle: Paclitaxel 90 mg/m 2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15 Miller et al. SABCS 2005

16 Improved PFS with Bevacizumab Added to Paclitaxel 1.0 Pac. + Bev months Paclitaxel 6.11 months 0.8 PFS Probability HR = 0.51 ( ) 0.62) Log Rank Test p< Miller K, SABCS Months 484 events reported

17 Bevacizumab in Clinical Subsets Group ER+, PR+ ER+, PR- ER-, PR- No adj chemo Non-taxane Taxane Age Age Age DFI 0-24 mos. DFI > 24 mos. < 3 sites 3 or more sites Overall Ratio 95% Conf Int (0.29, 0.53) (0.52, 1.43) (0.35, 0.63) (0.44, 0.82) (0.39, 0.67) (0.25, 0.59) (0.32, 0.63) (0.33, 0.58) (0.53, 1.17) (0.43, 0.75) (0.37, 0.60) (0.37, 0.61) (0.41, 0.71) (0.43, 0.62)