triple negative breast cancer
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The document discusses classification and treatment of triple negative breast cancer (TNBC). It begins with an overview of TNBC classification including molecular subtypes. It then describes the clinical characteristics and prognosis of TNBC compared to other breast cancer types. Treatment options discussed include chemotherapy with taxanes and platinum agents shown to be effective. Other potential targeted therapies mentioned include PARP inhibitors, EGFR inhibitors, angiogenesis inhibitors, and tyrosine kinase inhibitors.
![Chemosensitivity: Pathologic complete response (complete tumor eradication) to
preoperative chemotherapy [9, 10].
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press](https://image.slidesharecdn.com/incan-150418135237-conversion-gate02/85/triple-negative-breast-cancer-40-320.jpg)
triple negative breast cancer
- 2. Clasificacion Genomica Diferentes Tipos de TNBC Importancia de la Clasificacion Caracteristicas Clinicas del TNBC Opciones de Tratamiento Opciones a Futuro
- 3. Cancer Growth and Metastases
- 4. Histologia del cancer de mama Tipo Histológico Frecuencia (%) Supervivencia a 5 años (%) Carcinoma Ductal Infiltrante 63.6 79 Carcinoma Lobulillar infiltrante 5.9 84 Carcinoma Ductal & Lobular Infiltrante 1.6 85 Carcinoma Medular 2.8 82 Carcinoma Mucinoso 2.1 95 Comedocarcinoma 1.4 87 Enfermedad de Paget 1.0 79 Adenocarcinoma No Esp. 7.5 65
- 6. TRATAMIENTO SISTÉMICO DEL CÁNCER DE MAMA METASTÁSICO CON HER2 NORMAL
- 7. . Adapted from Hanahan and Weinberg. Cell. 2000;100:57. Evading apoptosis Self-sufficiency in growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis Insensitivity to antigrowth signals Cancer cells Fundamental Hallmarks of Cancer
- 10. Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844 Luminal Epithelial Cells Low molecular wt CK 7, 8, 18 and 19 Mucin, BCL2, Hormone Receptors Basal Cells (Myoepithelial cells) High molecular wt CK 5, 6, 14 and 17 SMA, Calponina, p63, P-caderin Perou C, et al. Nature 460:747-752, 2000 Terminal Duct Lobular Unit (TDLU)
- 11. Overall and relapse-free survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification. Therese Sørlie et al. PNAS 2001;98:10869-10874 ©2001 by National Academy of Sciences
- 13. Clasificación molecular del Cancer de Mama 6 biomarcadores: 1. RE 2. RP 3. HER2 4. EGFR 5. CK5/6 6. Ki67 SJ Schnitt et al - 2010 St. Gallen 2011: 1. RE 2. RP 3. HER2 4. Ki67
- 14. Why is subtype important? • Different outcomes • Prognostic significance • Selection of therapeutic options • Response to treatment
- 16. Hipótesis I: cada subtipo tiene SU célula de origen Polyak K - 2007
- 17. Hipótesis II: una sola célula de origen para todos los subtipos, y el fenotipo, determinado por eventos genéticos y epigenéticos. Polyak K - 2007
- 18. New Developments in Metastatic Breast Cancer Metzger-Filho O, et al. J Clin Oncol. 2012;30:1879-1887. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved. Heterogeneities in the Nomenclature and Classification of TNBC EGFR and cytokeratins Claudin-low subtype Basal-like tumors TNBC ER-negative PgR-negative HER2- negative BRCA1 mutant and BRCAness Immune system Different histologic subtypes
- 19. Clasificación molecular del CMTN: Subtipo “basal - like” Perou CM, 2010
- 20. Perou CM, 2010 Clasificación molecular del CMTN: Subtipo “claudin – low”
- 21. Aclarando conceptos… Chacon R - 2010
- 22. Triple Negative Basal ~75% of TNBC have Basal gene expression 1. Pal & Mortimer. Maturitas 2009; 2. Gluz et al. Ann Oncol 2009; 3. Anders & Carey. Oncology 2008. 4. Young et al. BMC Cancer 2009 5. Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018 Triple-Negative vs. Basal-Like: Definitions ER- / PR- / HER2- ~15% of all breast carcinomas Poorly differentiated Express CK 5/6, 17, EGFR (+) • BRCA1-2 mutated tumors •~5% of Breast Cancer • 50% BRCA-1 carriers are basal-like • Basal but not triple negative • Definition by gene expression • Includes most BRCA1 mutated tumors • 15-40% are ER+, PR+ or HER2+ • Triple negative but not basal • Definition by IHC • Includes other histologies (medullar, adenoid cystic) • 10-30% can also include “claudin- low,” a subtype notable for high expression of stem cell markers • 90% of TNBC do not have BRCA mutations BRCA 1-2
- 23. “BRCAness”: Characteristics shared between BRCA-associated and sporadic breast cancers. Lisa A. Carey The Oncologist 2011;16:71-78 ©2011 by AlphaMed Press
- 24. Lehmann B, et al. JCI, 121:2750, 2011
- 25. Prat A, Perou CM, 2009 En resumen…. (con respecto a la clasificación)
- 26. New Developments in Metastatic Breast Cancer What Is a Triple-Negative Breast Cancer (TNBC)? “Triple negative”: ER negative, PgR negative, HER2 negative – Depending on thresholds used to define ER and PgR positivity and methods for HER2 testing TNBC accounts for 10% to 17% of all breast carcinomas Significantly more aggressive than other molecular subtype tumors Majority grade 3 tumors Most frequently high grade invasive ductal carcinomas of no special type Reis-Filho JS, et al. Histopathology. 2008;52:108-118.
- 27. Any woman can get any type of breast cancer
- 28. Epidemiology Carey LA et al - 2006 Carolina Breast Cancer Study n = 1.424
- 29. New Developments in Metastatic Breast Cancer Characteristics and Features of TNBC Phenotype Weak relationship between tumor size and nodal status Rapid rise in risk of recurrence following diagnosis Peak risk of recurrence at 1-3 yrs Distant recurrence rarely preceded by local recurrence Local recurrence not predictive of distant recurrence Increased mortality rate first 5 yrs Majority of deaths occurs within first 5 yrs Rapid progression from distant recurrence to death Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.
- 30. New Developments in Metastatic Breast Cancer Clinical Characteristic of Metastatic TNBC No consistent association with nodal status or stage Relapse pattern – Higher risk – Early timing – Sites differ from luminal: – CNS 46% of time n Bone, % Soft Tissue, % Viscera, % TNBC 79 13 13 74 ER+ 123 39 7 54 HER2+ 78 7 12 81 Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Lin NU, et al. Cancer. 2008;113:2638-2645. 0.35 0.30 0.25 0.15 0.10 0.05 0 HR 0.20 0 1 2 3 4 5 6 7 8 9 10 Yrs After First Surgery Other (290 of 1421) Triple negative (61 of 180)
- 31. Rates of distant recurrences in triple- negative and other breast cancers. Dent R et al. Clin Cancer Res 2007;13:4429-4434 ©2007 by American Association for Cancer Research
- 33. Opciones de manejo Ca de mama RE/P (+) Ca de mama HER2 (3+) Cirugía Neoadyuvancia /adyuvancia (antraciclinas – taxanos) Radioterapia +/- Terapia endócrina (5 años) Recaída: hormonoterapia 2da y 3era linea Cirugía Neo Ady (antraciclinas – taxanos Trastuzuma/Pertuzumab) Radioterapia +/- Recaída: ( Kadcyla, capecitabina, lapatinib, gemcitabina,vinorelbine, eribulina, ixabepilona, etc)
- 34. Myths about triple negative breast cancer • There are no effective treatments. • Patients are doomed to relapse. • Women with triple negative cancers are doomed to die of their disease. • You have to have a mastectomy for triple negative breast cancer.
- 35. Opciones de manejo Ca de mama Triple (-) • Cirugía • Neoadyuvancia /adyuvancia (antraciclinas – taxanos) • Radioterapia +/- • Recaída ( capecitabina, platinos, • gemcitabina, inhib. de PARP • Bevacizumab, PIK3, PDL1. • Terapia endócrina NO • Terapia dirigida NO
- 36. Johnston S R Clin Cancer Res 2010;16:1979-1987 ©2010 by American Association for Cancer Research Targeted Therapies
- 37. Numberofsampleswithaberrations PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs 0 10 20 30 40 TSC1 PIK3CA PTEN PIK3R1 RICTOR RAPTOR AKT1 AKT2 AKT3 BRCA1 BRCA2 ATM RB1 AURKA CDNK2A CCNE1 CCND3 CCND2 CCND1 CDK6 CDK4 NF1 CRAF BRAF KRAS EGFR MET IGF1R KIT FGFR1 FGFR2 FGFR4 PI3K/mTOR inhibitors Targeted RTK inhibitors DNA-repair targeting agents Cell cycle/mitotic spindle inhibitors RAF/MEK inhibitors Arteaga C, et al. Vanderbilt Clinically targetable pathways in TNBC ~90% of all patients had an aberration in at least one of these pathways
- 38. Triple Negative Breast Cancer Treatment • Chemotherapy • Parp inhibitors • EGFR inhibitors • Angiogenesis inhibitors • Tyrosine Kinase inhibitors
- 39. Effectiveness of Chemotherapy Triple Negative / Basal Disease
- 40. Chemosensitivity: Pathologic complete response (complete tumor eradication) to preoperative chemotherapy [9, 10]. Lisa A. Carey The Oncologist 2011;16:71-78 ©2011 by AlphaMed Press
- 42. Basal-like BC Responds to Conventional Chemotherapy T-FAC (N=82)* AC-T (n=107)* Luminal A/B 7% 7% Normal-like 0 NA HER2+/ER- 45% 36% Basal-like/triple negative 45% 26% Rouzier, et al. Clin Cancer Res, 2005 Carey LA, et al. Clin Cancer Res 2007 • Basal-like / triple negative breast cancer responds to primary chemotherapy. Explanation of higher response but worse outcome? Pathologic Complete Response:
- 43. Responsiveness to conventional chemotherapy. Lisa A. Carey The Oncologist 2011;16:71-78 ©2011 by AlphaMed Press
- 44. Opciones de manejo: Platinos Silver, DP et al - 2010
- 45. The Role of Carboplatin in TNBC (Neo) Trial N Standard Chemotherapy Chemo + Carboplatin P-value CALGB 40603 443 41% 54% 0.003 I-SPY 2 NA 26% 52% 90% prob. for superiority GeparSixto (TNBC pts) 315 38% 59% <0.05 Sikov W, et al. SABCS 2013. Rugo H, et al. SABCS 2013. Von Minckwitz G, et al, The Lancet Oncology 15:747, 2014.
- 46. Opciones de manejo: Platinos Silver, DP et al - 2010 Utilidad en BRCA (+)
- 47. Adjuvant therapy for early breast cancer (90% are early at diagnosis). Lisa A. Carey The Oncologist 2011;16:71-78 ©2011 by AlphaMed Press
- 48. Rates of breast-specific survival in triple- negative and other breast cancers. Dent R et al. Clin Cancer Res 2007;13:4429-4434 ©2007 by American Association for Cancer Research
- 49. Rates of distant recurrences following surgery in triple-negative and other breast cancers. Dent R et al. Clin Cancer Res 2007;13:4429-4434 ©2007 by American Association for Cancer Research
- 50. Angiogenesis Taxol + Avastin in metastatic patients Benefit in triple negative patients
- 51. ECOG 2100: Randomized phase III trial of bevacizumab added to paclitaxel in stage IV breast cancer. Lisa A. Carey The Oncologist 2011;16:71-78 ©2011 by AlphaMed Press
- 52. Opciones de manejo: Bevacizumab Hudis CA, Gianni L - 2011 Beneficio en pacientes Triple Negativo
- 53. TNBC Patients ER 1-10% (6%) Age <60 83% T2-T3 86% LN+ 55% Grade III 86% CALGB/Alliance 40603 pCR in Breast and Axilla Sikov W, et al. SABCS 2013
- 54. Opciones de manejo: Ixabepilona Pacientes MTTS resistentes o progresadas a antraciclinas y taxanos. Hudis CA, Gianni L - 2011
- 55. Study Schema Carboplatin AUC5 q3wks x 4 Paclitaxel 80 mg/m2 qwk x 12 CP-CEF P-CEF HER2 (-) BC Stage II/IIIA 18-70 years PS 0/1 Good Organ function Written IC SURGERY CEF 500/100/500 mg/m2 q3wks x 4 R CEF 500/100/500 mg/m2 q3wks x 4 Paclitaxel 80 mg/m2 qwk x 12 Enrolled 181 pts N= 75 for TNBC 56% Node positive
- 56. pCR rates 32% 17% 0 20 40 60 80 100 CP-CEF P-CEFpCRrate(%) All patients 62% 26% 0 20 40 60 80 100 CP-CEF P-CEF pCRrate(%) TNBC patients Primary Endpoint P =0.04 pCR rates by EGFR expression EGFR- EGFR+ p=0.010 (%) 0 All AllCP CPP P 11.5 18.2 6.7 45.0 63.6 22.2 20 40 60 80 p=0.040 p= N.S. pCRrate Results
- 57. PARP Inhibitors in Development • Olaparib (Astra Zeneca) PO • Veliparib (ABT888 - Abbvie) PO • BMN-673 (Biomarin) PO • Niraparib (MK-4827) PO • CEP 9722 (Cephalon) PO • GPI 21016 (MGI Pharma) PO • Iniparib (BSI 201 – Sanofi-Aventis) IV • Rucaparib aka AGO 14699 (Pfizer) IV • INO 1001 (Inotek – Genentech/Roche) IV • Others?
- 58. Opciones de manejo: Inhibidores del PARP PARP 1: Prot. nuclear que va al sitio donde se halla el DNA dañado y cataliza la transferencia de ADP-ribosas del NAD+ para modular la reparación del DNA. Paciente con BRCA mutado: No tienen mecanismo de reparación del DNA por este medio.
- 59. Opciones de manejo: Inhibidores de PARP DNA DNA dañado REPARACIÓN BRCA Reposición de nucleótidos EVENTO MUTADO PARP
- 60. Mechanisms of Synthetic Lethality-PARP-1 60 Image from: Iglehart JD, Silver DP. Synthetic Lethality-A new direction in cancer-drug development. NEJM 2009; 361 (2) ; 189-191. 2009 Massachusetts Medical Society. All rights reserved. Permission requested.
- 61. Rugo H, et al. SABCS 2013 I-Spy 2 Trial Neoadjuvant Veliparib/Carboplatin followed by wPac/AC
- 62. Parp Inhibitors One trial in metastatic TNBC patients. Gemcitabine/carboplatin Improvement in tumor response and survival with Parp inhibitors
- 63. Opciones de manejo: Inhibidores de PARP DNA DNA dañado REPARACIÓN BRCA Reposición de nucleótidos EVENTO MUTADO PARP Inhibidor del PARP
- 64. Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + New Agent C Patient is on Study Paclitaxel+ Trastuzumab Paclitaxel + Trastuzumab* + New Agent B Paclitaxel Paclitaxel + New Agent E AC ACHER 2 (+) HER 2 (–) Randomize Randomize Surgery Surgery Learn and adapt from each patient as we go along Paclitaxel + New Agent F Paclitaxel + Trastuzumab* + New Agent C Paclitaxel + New Agent D Paclitaxel + New Agent GH Paclitaxel + Trastuzumab* + New Agent F MRI Residual Disease (Pathology) Key 64 I-SPY 2 TRIAL: Learn, Drop, Graduate, and Replace Agents Over Time
- 65. Veliparib/Carboplatin GRADUATES in the Triple Negative Signature SIGNATURE Estimated pCR Rate (95% probability interval) Probability Veliparib + Carbo is Superior to Control Predictive Probability of Success in Phase 3 Veliparib/ Carbo Concurrent Control All HER2- 33% (22-43%) 22% (10-35%) 92% 55% HR+/HER2- 14% (4-27%) 19% (6-35%) 28% 9% HR-/HER2- 52% (35-69%) 26% (11-40%) 99% 90% Rugo et. al. SABCS 2013
- 66. EGFR inhibitors Two trials in metastatic breast cancer Irinotecan/carboplatin + cetuximab Cetuximab alone or with carboplatin
- 67. EGFR Inhibition for TNBC • TNBC is strongly associated with EGFR expression • EGFR inhibitors combined with platinum • Current data are conflicting TBCRC 001 (n=102) O’Shaugnessy et al (n=78) Cetuximab Carboplatin + Cetuximab Irinotecan + Carboplatin Irinotecan + Carboplatin + Cetuximab ORR,% 6 18 49 30 Clinical benefit, % 10 27 NR NR PFS, mo 2 5.1 4.7 Efficacy data from phase II trials NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium Carey et al. ASCO 2008; abstr 1009; O’Shaughnessy et al. SABCS 2007; abstr 308.
- 68. TNBC recent perspectives Looking for a target... • Other Chemotherapy? • Androgen Receptor • PI3K pathway alterations • EGFR inhibitors • Anti-angiogenics • Src inhibitors • C-Kit alteration • Clinical Trail • Likely will need combos
- 69. Opciones de manejo: Otras “potenciales” opciones 1. Anti – EGFR: cetuximab 2. Inhibidores de Tirosin- kinasa: sunitinib 3. Anti – mTOR: everolimus 4. Antiandrógenos: bicalutamida Santana-Davila R, Pérez EA - 2010
- 70. TNBC: potential therapeutic targets Mayer I A et al. Clin Cancer Res 2014;20:782-790 ©2014 by American Association for Cancer Research
- 71. SWOG Proposed Study R TNBC Post NAC PT1C or N+ N=400 Placebo x 1 year MK3475 x 1 year Anti-PD1 antibody Primary endpoint: DFS A randomized, phase III trial to evaluate the efficacy and safety of MK- 3475 as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy
- 72. SAFIR 01 Study Outcomes Andre F, et al. Lancet Oncol 2014 Targets addressed: • PI3KCA mutation • EGFR amplification • AKT mutation • FGFR amplification • IGF-1R amplification Overall Benefit Rate:12/407 (3%)Response Rate: 4/407 (1%) 17 Targeted Regimens
- 73. Novel Agents in Development for TNBC • Met inhibitor: ARQ197, onartuzumab (Metmab), foretinib • PI3K and/or inhibitor: BKM 120, temsirolimus (+ neratinib) • HDAC inhibitors: entinostat, vorinosat • Demethylating agents: azacitidine (+ entinostat) • PARP inhibitors: ABT-888, E7449, Biomarin-BMN673, AZD2281, rucaparib • Olaparib+ BKM120; • Angiogenesis inhibitor: cediranib (+ olaparib), ramicurumab, IMC18F1, foretenib, sorafenib • Hsp90 inhibitors: ganetespib • Aurora kinase inhibitors: ENMD 2076 • Androgen Receptor Blockers: enzalutamide • EGF inhibitors: erlotinib (+ metformin), apatanib • Lucitanib (FGFR+VEGF inhibitor) • Masitinib (C-Kit inhibitor) • MEK inhibitors: GSK1120212 • Wnt inhibitor: LGK974 • CDK inhibitor: dinaciclib, P276-00 • FMS-Kit inhibitor: PLX3397 • Apoptosis inducer: LCL161 (deactivating inhibitor of apoptosis proteins) • Immunotherapy: MUC1 vaccine, adoptive cellular therapy (DC-CIK) • Cytotoxics: SN38 -NK012, AEZS-108 (LHRH-dox); • Checkpoint inhibitors (anti PD-1, anti PDL-1)
- 74. TNBC: Conclusions • TNBC is a recognized distinct subtype of BC – ER, PR, HER2-negative by IHC • Surrogate of basal-like BC – More aggressive biology (morphology, clinical, molecular) • TNBC responds to a variety of CT agents although no specific standard regimen or agent can be singled out • TNBC has no identified specific therapeutic target • Represents an heterogeneous group of tumors probably with different response patterns to different treatments – Introduction of novel agents (PARPi, others) ? – Biomarkers: RAD-51, Neuropilin ?
- 75. En conclusión… • Presente como cáncer de intervalo • Poca asociación entre tamaño de tumor y estado axilar. • Metástasis tempranas y agresivas. • Recurrencia pico entre 1º y 3º años del diagnóstico. • La recurrencia local no predice recaída a distancia.
- 76. En conclusión… • Más prevalente en jóvenes. • Fuerte asociación con obesidad. • Alta prevalencia de mets cerebrales. • La mayoría de las muertes son a 5 años. • Altamente quimiosensible. • Todos los tratamientos en estudios.
- 77. Triple Negative Breast Cancer • Represents a subtype of breast cancer with unique molecular and clinical characteristics . • Characterized by more aggressive clinicopathologic features including younger age, higher mean tumor size, and higher-grade tumors . • More likely to occur among premenopausal women of African-American descent . • Association with BRCA1 mutation status. • More likely to develop a recurrence during the first 3 years following therapy • More aggressive visceral and soft-tissue relapse and less common bone recurrence. • High response to systemic chemotherapy. 103
- 78. Future Directions • Increase participation in clinical trials. • Design and implement cancer prevention trials applicable to at risk populations. • Increase understanding of risk factors and biology underlying triple-negative breast cancer. • Improving treatment strategies. • Continuous review of current methods. 104