Relevancia práctica de la clasificación de subtipos intrínsecos en cáncer de mama Miguel Martín Instituto de Investigación Sanitaria Gregorio Marañón

Relevancia práctica de la clasificación de subtipos intrínsecos en cáncer de mama Miguel Martín Instituto de Investigación Sanitaria Gregorio Marañón Universidad Complutense Madrid

The new technologies have changed our understanding of breast cancer XIX century 1980s 1990s XXI century HE morphology/ histology IHC single genes FISH DNA/RNA arrays SNP analysis Multiplex PCR NGS TECHNOLOGY multiple genes

Molecular portraits of human breast tumors The intrinsic subtype classification Perou CM et al, Nature 406:747,2000

Comprehensive molecular portraits of human breast tumors The Cancer Genome Atlas Network Gen Mutado Integration of information across 5 platforms confirmed the existence of 4 main breast cancer classes TP53 187 (37%) PIK3CA 180 (36%) GATA3 54 (11%) MAP3K1 39 (8%) MLL3 37 (7%) CDH1 33 (6.5%) MAP2K4 21 (4%) RUNX1 18 (3.5%) PTEN 17 (3.4%) TBX3 13 (2.5%) doi:10.1038/nature11412

The Oncologist 2015;20:474 482

Conclusion Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. The Oncologist 2015;20:474 482

Distribution of PAM50 intrinsic subtype across IHC-based biomarkers (N=1396, Both Centrally Determined) Data from: TAMseries (CCR 2010), GEICAM 9906 (JCO 2013) and GEICAM 2012-09 (CMRO 2015) Ki-67 PR 0-10% 11-20% 21-30% >30% N % N % N % N % LumA 620 70.1% 112 34% 28 20% 4 10% LumB 265 29.9% 219 66% 112 80% 36 90% 0-10% 11-90% 91-100% N % N % N % LumA 243 42.1% 347 58% 160 73% LumB 334 57.9% 249 42% 59 27% 30-40%?? ER Cortesy: A. Prat 0-10% 11-90% 91-100% N % N % N % LumA 93 48% 378 53% 267 58% LumB 100 52% 333 47% 196 42%

The Oncologist 2013;18:123 133

Conclusions The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Bastien et al. BMC Medical Genomics 2012, 5:44

Plataformas Genómicas en Cáncer de Mama Oncotype Dx (Genomic Health, 21 genes) Mammaprint (Agendia, 70 genes) Prosigna TM (Nanostring, 50 genes-pam50) EndoPredict (Sividon, 12 genes) Map-Quant Dx (Ipsogen, 97 genes) Breast Cancer Index/Theros (Biotheranostics, 2 genes)

Genomic platforms:potenial clinical applications in breast cancer prognostication prediction of response to hormones prediction of response to chemotherapy Prediction of response to specific CT drugs Prediction of response to targeted therapies

Genomic platforms:potenial clinical applications in breast cancer prognostication

Proportion without Distant Recurrence Oncotype DX : B-14 Results Distant Recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% RS <18 n = 338 RS 18-30 n = 149 RS 31 n = 181 P <0.001 Riesgo de recurrencia a los 10 años Bajo riesgo (6.8%) Riesgo intermedio (14.3%) Alto riesgo (30.5%) 0 2 4 6 8 10 12 14 16 Years Paik et al. N Engl J Med. 2004;351:2817-2826.

Mammaprint 78 breast tumors Age < 55 years, Tumor size < 5 cm Lymph node negative & No adjuvant therapy Distant metastases within 5 years No distant metastases for at least 5 years 43% Low Risk Signature CLASSIFICATION THRESHOLD High Risk Signature van t Veer L et al., Nature, 2002; Van de Vijver M et al; N Engl J Med 347:1999,2002

Mammaprint: TRANSBIG Validation Results 15% Buyse et al (2006) J Natl Cancer Inst 17;1183-1192

EP Score 92% MFS EPclin Score 100% MFS Martin et al., Breast Cancer Res Treat (2016) 156:81 89

ABCSG-8 trial

Genomic platforms:potenial clinical applications in breast cancer prognostication prediction of response to hormones

Tamoxifen Benefit and Oncotype DX NSABP B-14 Tam Benefit Study in N, ER+ Patients Design Randomized Placebo-Eligible Tam-Eligible Objective: Determine whether the 21-gene RS assay provides predictive information for patients who were treated with tamoxifen (likelihood of recurrence) Paik et al. ASCO 2004. Abstract #510.

B-14 Benefit of Tamoxifen By Recurrence Score Risk Category

B-14 Benefit of Tamoxifen By Recurrence Score Risk Category

Prognostic value of PAM50 and risk of recurrence score in patients with earlystage breast cancer with long-termfollow-up Observational Oslo1 study (1995 1998) Ohnstad et al. Breast Cancer Research (2017) 19:120

Prognostic value of PAM50 and risk of recurrence score in patients with earlystage breast cancer with long-term follow-up Ohnstad et al. Breast Cancer Research (2017) 19:120

Genomic platforms:potenial clinical applications in breast cancer prognostication prediction of response to hormones prediction of response to chemotherapy

Prognostication and prediction are linked in ER+/HER2- breast cancer

Chemotherapy Benefit and Oncotype DX NSABP B-20 Tam + MF Randomized Tam + CMF Tam Paik et al. J Clin Oncol. 2006;24:3726-3734.

High Recurrence Score result correlates with greater benefit from chemotherapy (NSABP B-20) Overall, 4.4% absolute benefit from tamoxifen + chemotherapy Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

High Recurrence Score result correlates with greater benefit from chemotherapy (NSABP B-20) Overall, 4.4% absolute benefit from tamoxifen + chemotherapy LOW RS GROUP Recurrence Score <18 28% absolute benefit INTERMEDIATE RS GROUP Recurrence Score 18-30 HIGH RS (>30) Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Number of Patients Needed to Treat (NNT) to Avoid a Distant Recurrence with tamoxifen + CT vs tamoxifen alone (NSABP B-20) NNT 22.7 3.6 Population Distant Recurrence Rate with tamoxifen Distant Recurrence Rate with tamoxifen + chemotherapy All patients 12% 8% High RS 40% 12%

Pathologic complete response to neoadjuvant chemotherapy differs by subtype T-FAC 1 (N=82) AC-T 2 (n=107) Luminal A/B 2/30 (7%) 4/62 (7%) Normal-like 0/10 (0) NA HER2+/ER- 9/20 (45%) 4/11 (36%) Basal-like 10/22 (45%) 9/34 (26%) P<0.001 P=0.003 1 Rouzier R, Clin Cancer Res 2005; 2 Carey LA, Clin Cancer Res, 2007

Genomic platforms: potential clinical applications in breast cancer prognostication prediction of response to hormones prediction of response to chemotherapy Prediction of response to specific CT drugs Prediction of response to targeted therapies

Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial Premenopausal N+ (n=710) CMFx6 CEFx6 Levine MN, et al. J Clin Oncol. 2005;23:5166;.

Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial Premenopausal N+ (n=710) CMFx6 CEFx6 Levine MN, et al. J Clin Oncol. 2005;23:5166; Cheang M et al, Clin Cancer Res 18:2402.

Respuesta a quimioterapia neoadyuvante con docetaxel+carboplatino en cáncer de mama triple negativo (n=96) Distribución subtipo intrínseco 1% 3% Respuesta global (Symmans) 13% Basal HER2E LumB 30,9% 12,8% 44,7% pcr RCB-I RCB-II 83% Normal 11,7% RCB-III Isabel Echavarría, Tesis Doctoral, UCM 2017

Respuesta a quimioterapia neoadyuvante con docetaxel+carboplatino en cáncer de mama triple negativo Distribución subtipo intrínseco 1% 3% Respuesta global (Symmans) 13% Basal 12,8% HER2E 44,7% pcr RCB-I LumB 30,9% RCB-II 83% Normal RCB-III 11,7% 100% 90% 80% 70% 9,00% 29,50% 31,30% 60% 50% 40% 10,30% p=0,007 37,50% 30% 20% 51,30% 18,80% 10% 0% Basal 12,50% No-basal pcr RCB-I RCB-II RCB-III Isabel Echavarría, Tesis Doctoral, UCM 2017

Genomic platforms:potenial clinical applications in breast cancer prognostication prediction of response to hormones prediction of response to chemotherapy Prediction of response to specific CT drugs Prediction of response to targeted therapies