Ponencia a favor: terapia neoadyuvante dirigida por genómica en la era COVID19
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Actividad académica (independiente) de la Asociación de Mastología de Antioquia (AMA), realizada en 07/05/2020. Se trató de un debate sobre la pertinencia del uso de pruebas genómicas preoperatorias para definir terapia neoadyuvante con quimioterapia o terapia endocrina en pacientes con cáncer de mama temprano en la era del COVID19, entre Mauricio Lema y Andrés Yepes. El escenario hipotético es: "Mujer de 58 años con cáncer de mama cT1c cN0 cM0, luminal A, en un entorno donde la cirugía inmediata no es una opción".
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Ponencia a favor: terapia neoadyuvante dirigida por genómica en la era COVID19
- 1. Uso de pruebas genómicas para dirigir la terapia neoadyuvante en cáncer de mama luminal, en la era del COVID-19 A favor Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA, Medellín
- 2. Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA Medellín Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers
- 3. Conflictos de interés Mauricio Lema Medina ha recibido honorarios de Amarey y Genomic Health por concepto de: patrocinio para investigación clínica y conferencias Esta conferencia NO es patrocinada por nadie. 05.2020
- 4. Preparación Contención No mucho cambio en las indicaciones Disminuir umbral para terapia neoadyuvante sistémica Recomendaciones COVID-19 y cáncer de mama en Colombia - AMA, ACM, ACHO, ACRO, ACR – 03.04.2020 COVID19 y manejo de cáncer de mama Fase Recomendación Desbordada Diferir manejo quirúrgico
- 5. Contención Disminuir umbral para terapia neoadyuvante sistémica Recomendaciones COVID-19 y cáncer de mama en Colombia - AMA, ACM, ACHO, ACRO, ACR – 03.04.2020 COVID19 y manejo de cáncer de mama Fase Recomendación Estadíos III, N voluminosos Triple negativos / HER2+ N+ T1-2 N0 luminales Considerar terapia sistémica neoadyuvante
- 6. Mujer 58 años de edad Cáncer de mama: ductal infiltrante Grado 2 Unifocal 15 mm de diámetro (T1c) cN0 Receptores de estrógeno 100% Receptores de progesterona 100% Her2: 0 Ki67: 10%
- 7. El problema
- 8. COVID19
- 9. T1cN0M0 – Estadío IA Luminal A Cirugía Prueba genómica pT1c cN0(sn) Quimio A Radioterapia RS alto RS bajo Quimio NA Preservadora de la mama Ganglio centinela T. Endocrina Radioterapia Cirugía ypT1b cN0(sn) Preservadora de la mama Ganglio centinela Radioterapia Opciones VÁLIDAS
- 10. T1cN0M0 – Estadío IA Luminal A Cirugía Prueba genómica pT1c cN0(sn) Quimio A Radioterapia RS alto RS bajo Quimio NA Preservadora de la mama Ganglio centinela T. Endocrina Radioterapia Cirugía ypT1b cN0(sn) Preservadora de la mama Ganglio centinela Radioterapia Opciones VÁLIDAS 20% 80% Sparano et al. N Engl J Med. 2018
- 11. T1cN0M0 – Estadío IA Luminal A COVID19 Quimio NA Cirugía ypT1b cN0(sn) Radioterapia
- 12. T1cN0M0 – Estadío IA Luminal A COVID19 Quimio NA Cirugía ypT1b cN0(sn) Radioterapia T. Endocrina NA Cirugía ypT1b cN0(sn) Radioterapia Y el 20% que necesitaba quimio?
- 13. O se retrasa O todas reciben quimio O el 20% que necesitaba quimioterapia NO la recibe
- 14. T1cN0M0 – Estadío IA Luminal A Prueba genómica Quimio NA T. Endocrina NA RS alto RS bajo Cirugía, RT, etc… 20% 80% Propuesta COVID19 Semanas… meses (6, para ser exactos)
- 15. ¿Evidencia?
- 16. ¿Evidencia? Ahí está el $·#o problema
- 17. Requisitos Prueba que sugiera/demuestre futilidad de quimioterapia en un grupo específico de pacientes Prueba que sugiera/demuestre necesidad de quimioterapia en un grupo específico de pacientes Que la quimioterapia neoadyuvante sea una opción válida Que la terapia endocrina neoadyuvante sea una opción válida
- 18. T1cN0M0 – Estadío IA Luminal A Cirugía Quimio NA
- 19. ¿Existe algún subgrupo de pacientes con cáncer luminal que NO deriva beneficio de quimioterapia en enfermedad temprana?
- 20. ¿Qué pruebas genómicas de recurrencia son pronostican recaída 0-10 años en cáncer de mama temprano?
- 21. Recaída a distancia 0-10 años, ganglios negativos 1. Sestak I, JAMA Oncol, 2018 CTS: Clinical Treatment Score RS: OncoType RS score BCI: Breast Cancer Index ROR: ProSigna PAM50 score EpClin: EndoPredict Relacióndepeligro(HR) n=591 pacientes Trans-ATAC
- 22. Recaída a distancia 0-10 años, ganglios positivos 1. Sestak I, JAMA Oncol, 2018 CTS: Clinical Treatment Score RS: OncoType RS score BCI: Breast Cancer Index ROR: ProSigna PAM50 score EpClin: EndoPredict Relacióndepeligro(HR) n=227 pacientes Trans-ATAC
- 23. 2a ¿ Qué pruebas genómicas de recurrencia son pronostican recaída 0-10 años en cáncer de mama temprano? Todas las disponibles comercialmente: OncoType, BCI, EpClin… MAMMAPRINT
- 24. ¿Existe alguna prueba genómica de recurrencia con capacidad PREDICTIVA de respuesta a quimioterapia o terapia endocrina, con validación prospectiva?
- 25. Validación prospectiva CTS EpClin RS Mammaprint BCI ROR (PAM50)
- 26. Validación prospectiva CTS EpClin RS Mammaprint BCI ROR (PAM50)
- 27. Validación prospectiva CTS EpClin RS Mammaprint BCI ROR (PAM50)
- 29. Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70- gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy MINDACT Cardoso F, NEJM, 2016
- 30. Entre las mujeres con cáncer de mama en estadio temprano que tenían un alto riesgo clínico y un bajo riesgo genómico de recurrencia, la no administración de quimioterapia sobre la base de la firma de 70 genes dio lugar a una tasa de supervivencia de 5 años sin metástasis distante que fue 1,5 puntos porcentuales inferior a la tasa con quimioterapia MINDACT Cardoso F, NEJM, 2016 Google Translate
- 31. Entre las mujeres con cáncer de mama en estadio temprano que tenían un alto riesgo clínico y un bajo riesgo genómico de recurrencia, la no administración de quimioterapia sobre la base de la firma de 70 genes dio lugar a una tasa de supervivencia de 5 años sin metástasis distante que fue 1,5 puntos porcentuales inferior a la tasa con quimioterapia MINDACT Cardoso F, NEJM, 2016 Google Translate
- 35. N0 N1 N2 N3 M1 T0 Tis IIa IIIa IIIc IV T1 Ia IIa IIIa IIIc IV T2 IIa IIb IIIa IIIc IV T3 IIb IIIa IIIa IIIc IV T4 IIIb IIIb IIIb IIIc IV Receptores de estrógeno o progesterona positiva+ Her2 negativo Unifocal T (T1/2): >1 cm y ≤5 cm o >0.5-1 cm, grado 2/3 N0 M0
- 36. The Recurrence Score® Prognostic Risk Groups Defined for Distant Recurrence NSABP B-14: First Validation Study for Prognosis in Node-Negative Patient Population 36 Paik et al. N Engl J Med. 2004. Distant recurrence over time 10-year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 0 2 4 6 8 10 12 14 16 Years 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%Proportionwithoutdistantrecurrence RS <18, n = 338 RS 18-30, n = 149 RS ≥31, n = 181 All Patients, n = 668 P < .001 10-year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% *10-year distant recurrence comparison between low- and high-risk groups: P <.001. RS: Recurrence Score result
- 37. TAILORx Methods: Treatment Assignment and Randomization Accrued Between April 2006–October 2010 3 7 HR+/HER2-Negative Node-Negative Breast Cancer Oncotype DX® Test (N = 10,273) Arm A: Low RS 0-10 ET (N = 1629) Midrange RS 11-25 RANDOMIZE (N = 6711) Arm D: High RS 26-100 ET + Chemo (N = 1389) Arm B: Experimental Arm ET Alone (N = 3399) Arm C: Standard Arm ET + Chemo (N = 3312) ET: endocrine therapy HR: hormone receptor HER2: human epidermal growth factor receptor 2 RS: Recurrence Score® result Stratification factors: • Menopausal status • Planned chemotherapy • Planned radiation • RS 11-15, 16-20, 21-25 Sparano et al. J Clin Oncol. 2008.
- 38. TAILORx Results: Endocrine Therapy Alone Was Not Inferior to Chemoendocrine Therapy in Patients With RS 11-25 (Arms B & C) Primary Endpoint: 9-Year Invasive Disease-Free Survival (iDFS) in ITT Population 836 iDFS events after median follow-up of 7.5 years 3 8 ITT: intent-to-treat iDFS: invasive disease-free survival RS: Recurrence Score® results ET: endocrine therapySparano et al. N Engl J Med. 2018.
- 39. ≤50 years-old 21-gene recurrence score assay (OncoTypeDx) Luminal A or B (Her2-) >1-5 cm in size (T1c/2) or >0.5 cm Grade 2 or 3 N0M0 >50 years-old RSS 0-15 (LR) Adjuvant hormonal therapy (no CT) RSS 16-25 Adjuvant hormonal therapy, CT if RSS ≥20 or high clinical risk* RSS >25 (HR) Adjuvant CT and hormonal therapy *High clinical risk is defined as: Tumor >2 cm; or 1-2 cm, grade 2 or 3; or less ≤1 cm grade 3 RSS: Recurrence score (0-100) CT: Chemotherapy EBC: Early-Breast cancer
- 40. 21-gene recurrence score assay (OncoTypeDx) Luminal A or B (Her2-) >1-5 cm (T1c/2) o >0.5 cm Grade 2 or 3 N0M0 RS 0-25(LR) Terapia Endocrina (no quimioterapia) RS >25 (HR) Quimioterapia Terapia Endocrina RS: Recurrence score (0-100) CT: Chemotherapy EBC: Early-Breast cancer Mayores de 50 años de edad Sparano et al. N Engl J Med. 2018
- 41. 2b ¿Existe alguna prueba genómica de recurrencia con capacidad PREDICTIVA de respuesta a quimioterapia o terpia endocrina, con validación prospectiva? Sí, OncoType Dx (TAILORx)
- 42. 2 Sí - RS bajo ¿Existe algún subgrupo de pacientes con cáncer luminal que no deriva beneficio de quimioterapia en enfermedad temprana?
- 43. T1cN0M0 – Estadío IA Luminal A Cirugía OncoTypeDx pT1c cN0(sn) Radioterapia RS bajo Quimio NA Preservadora de la mama Ganglio centinela T. Endocrina Cirugía ypT1b cN0(sn) Preservadora de la mama Ganglio centinela Radioterapia Opciones VÁLIDAS 80% Sparano et al. N Engl J Med. 2018
- 44. ¿Existe algún subgrupo de pacientes con cáncer luminal que SÍ deriva beneficio de quimioterapia en enfermedad temprana?
- 45. The Breast Recurrence Score® Test Predicts Those Patients Who Do and Do Not Derive Benefit From Chemotherapy NSABP B-20: Second Validation Study for Prediction in Node-Negative Patient Population Paik et al. J Clin Oncol. 2006. RS: Recurrence Score resultYears PATIENTS WITH HIGH RS ≥31 28% absolute benefit from tamoxifen + chemotherapy Interaction P = 0.038 45 Events
- 46. The Breast Recurrence Score® Test Predicts Those Patients Who Do and Do Not Derive Benefit From Chemotherapy NSABP B-20: Second Validation Study for Prediction in Node-Negative Patient Population Paik et al. J Clin Oncol. 2006. RS: Recurrence Score resultYears PATIENTS WITH HIGH RS ≥31 28% absolute benefit from tamoxifen + chemotherapy Interaction P = 0.038 46
- 47. TAILORx Methods: Treatment Assignment and Randomization Accrued Between April 2006–October 2010 4 7 HR+/HER2-Negative Node-Negative Breast Cancer Oncotype DX® Test (N = 10,273) Arm A: Low RS 0-10 ET (N = 1629) Midrange RS 11-25 RANDOMIZE (N = 6711) Arm D: High RS 26-100 ET + Chemo (N = 1389) Arm B: Experimental Arm ET Alone (N = 3399) Arm C: Standard Arm ET + Chemo (N = 3312) ET: endocrine therapy HR: hormone receptor HER2: human epidermal growth factor receptor 2 RS: Recurrence Score® result Stratification factors: • Menopausal status • Planned chemotherapy • Planned radiation • RS 11-15, 16-20, 21-25 Sparano et al. J Clin Oncol. 2008.
- 48. TAILORx Results: Patients in Arms A, B & C With RS 0-25 Have ≤5% Risk of Distant Recurrence at 9 Years 9-Year Event Rates – ITT Population: All Arms 4 8 ET: endocrine therapy ITT: intent-to-treat RS: Recurrence Score® resultSparano et al. N Engl J Med. 2018. Patients in Arm D experienced a higher rate of distant recurrence at 13% despite chemoendocrine therapy
- 49. TAILORx Results: Patients in Arms A, B & C With RS 0-25 Have ≤5% Risk of Distant Recurrence at 9 Years 9-Year Event Rates – ITT Population: All Arms 4 9 ET: endocrine therapy ITT: intent-to-treat RS: Recurrence Score® resultSparano et al. N Engl J Med. 2018. Patients in Arm D experienced a higher rate of distant recurrence at 13% despite chemoendocrine therapy No haga esto en casa…
- 50. 3 Parece que SÍ (estudio retrospectivo, y TAILORx en no cohorte aleatorizada) ¿Existe algún subgrupo de pacientes con cáncer luminal que SÍ deriva beneficio de quimioterapia en enfermedad temprana?
- 51. T1cN0M0 – Estadío IA Luminal A Cirugía Prueba genómica pT1c cN0(sn) Quimio A RS alto Quimio NA Preservadora de la mama Ganglio centinela T. Endocrina Radioterapia Cirugía ypT1b cN0(sn) Preservadora de la mama Ganglio centinela Radioterapia Opciones VÁLIDAS 20% Sparano et al. N Engl J Med. 2018
- 52. ¿Cuánto tiempo se puede diferir la cirugía?
- 53. Bleicher RJ, Ann Surg Oncol, 2018 Impacto de intervalo diagnóstico – inicio de tratamiento
- 54. Bleicher RJ, Ann Surg Oncol, 2018 Impacto de intervalo diagnóstico – inicio de tratamiento Intervalo aceptable entre diagnóstico y cirugía ≤90 días ↓ supervivencia cáncer específica: 24% por mes, ↓ supervivencia global: 9-10% ↓ absoluta de supervivencia: 3.1-4-6% SEER-NCDB < 90 días > Intervalo aceptable entre diagnóstico y radioterapia ≤365 días
- 55. Bleicher RJ, Ann Surg Oncol, 2018 Impacto de intervalo diagnóstico – inicio de tratamiento Intervalo aceptable entre diagnóstico y quimioterapia 120 días (?) Biología Duración retraso (semanas) Afecta supervivencia? Magnitud Luminal A No establecido No No aplica Luminal B 8 Sí HR: 1.93 Triple negativo 6 Sí Considerar neoadyuvante como estándar HER2+ 6-12 semanas Sí (2 estudios), No (1 estudio)
- 56. 4 ¿Cuánto tiempo se puede diferir la cirugía? Más de lo que pensábamos; especialmente, si recibe terapia neoadyuvante
- 57. T1cN0M0 – Estadío IA Luminal A COVID19 No recomendable…
- 58. ¿Puede la quimioterapia neoadyuvante ser administrada en forma sistemática?
- 59. NSABP B-181 Cáncer de mama No metastásica No operadas 1. Fisher B, J Clin Oncol, 1997 R Doxorrubicina + ciclofosfamida Cirugía Cirugía Doxorrubicina + ciclofosfamida Desenlace principal: proporción de preservación de mama ↑12% la cirugía preservadora de la mama ↑175% la cirugía preservadora de la mama en tumores >5 cm N=1523
- 60. Análisis agrupado Quimioterapia Neoadyuvante vs Adyuvante1 Meta-análisis Quimioterapia neo vs adyuvante 9 estudios 3.940 pacientes 1. Mauri D, J Natl Cancer Inst, 2005 Desenlaces Muerte Progresión a distancia Pregunta de investigación: El impacto de la quimioterapia neoadyuvante en los desenlaces de supervivencia al compararala con adyuvante Progresión
- 61. Análisis agrupado Quimioterapia Neoadyuvante vs Adyuvante1 1. Mauri D, J Natl Cancer Inst, 2005 Google Graphs Candlestick Relacióndeprobabilidades(OR) Favorece quimioterapia neoadyuvante
- 62. 5 ¿Puede la quimioterapia neoadyuvante ser administrada en forma sistemática? Sí
- 63. T1cN0M0 – Estadío IA Luminal A Quimio NA Cirugía ypT1b cN0(sn) Radioterapia QUIMIO 100% Y la biología dice que sólo 20% la requieren… T. Endocrina
- 64. ¿Existe evidencia convincente de terapia endocrina neoadyuvante en cáncer de mama luminal?
- 65. T1cN0M0 – Estadío IA Luminal A T. Endocrina NA Cirugía ypT1b cN0(sn) Radioterapia T. Endocrina
- 66. Análisis agrupado Terapia Endocrina Neoadyuvante1 Meta-análisis Quimioterapia neo vs adyuvante 20 estudios 3.490 pacientes 1. Spring LM, JAMA Oncol, 2016 Desenlaces Preservación de mama Tasa de respuesta Pregunta de investigación: Evaluar los efectos de terapia endocrina neoadyuvante en la preservación de mama y la tasa de respuesta.
- 67. Análisis agrupado Terapia Endocrina Neoadyuvante1 1. Spring LM, JAMA Oncol, 2016 AI RR: Tasa de respuesta con inhibidores de aromatasa AI radRR: Tasa de respuesta radiológica con inhibidores de aromatasa BCS: Preservación de la mama con inhibidores de aromatasa Google Graphs Candlestick Relacióndeprobabilidades(OR) 1.08 1.38 0.65 Favorece terapia endocrina
- 68. Análisis agrupado Terapia Endocrina Neoadyuvante1 1. Spring LM, JAMA Oncol, 2016 RR: Tasa de respuesta AI radRR: Tasa de respuesta radiológica BCS: Preservación de la mama Relacióndeprobabilidades(OR) 1.69 1.49 1.62 Favorece Inhibidor de Aromatasa al compararla con Tamoxifén
- 69. Terapia endocrina comparada con quimioterapia neoadyuvante1 1. Spring LM, JAMA Oncol, 2016 Estudio N Brazos Tasa de respuesta Comentarios T. endocrina Quimioterapia Alba 95 Exemestano vs A+T 48% 66% NS Palmieri 44 Letrozol vs A+T 59.1% 54.% NS Semiglazov 239 Anastrozol vs A+T 64% 64% NS: sin significancia estadística.
- 70. 6 ¿Existe evidencia convincente de terapia endocrina neoadyuvante en cáncer de mama luminal? Sí (menos convincente de lo que pensé), y claramente con INHIBIDORES DE AROMATASA
- 71. T1cN0M0 – Estadío IA Luminal A T. Endocrina NA Cirugía ypT1b cN0(sn) Radioterapia T. Endocrina T. Endocrina neoadyuvante 100% Y la biología dice que 20% requieren quimioterapia
- 72. Falso o verdadero: RS alto riesgo preoperatorio se asocia a menor respuesta a terapia endocrina neoadyuvante
- 73. OncoType Dx preoperatorio1 ER+ / Her2- T2, estadío III, N0-2 55-75 años de edad 1. Ueno T, Int J Clin Oncol, 2014 OncoType Dx Exemestano x 16 – 24 semanas Desenlace principal: Investigar la asociación de RS con la respuesta clínica a hormonoterapia neoadyuvante Cirugía OncoType Dx Grupo de riesgo N Respuesta clínica Cirugía preservadora de mama Bajo 32 59.4% 90.6% Intermedio 17 58.8% 76.5% Alto 15 20.0% 46.7% p=0.015 N=64 N=52
- 74. 7 Verdadero (estudio descriptivo) Falso o verdadero: RS alto riesgo preoperatorio se asocia a menor respuesta a terapia endocrina neoadyuvante
- 75. Requisitos Prueba que sugiera/demuestre futilidad de quimioterapia en un grupo específico de pacientes Prueba que sugiera/demuestre necesidad de quimioterapia en un grupo específico de pacientes Que la quimioterapia neoadyuvante sea una opción válida Que la terapia endocrina neoadyuvante sea una opción válida
- 77. Se obtiene el mejor de los mundos: se inicia tratamiento en forma oportuna, de difiere la cirugía en forma segura, se le administra quimioterapia a (la minoría) que lo necesita, y se le administra la terapia endocrina a las demás…
- 78. Propuesta de manejo en la era de COVID19: acceso limitado a cirugía Unifocal, luminal, T1b/c-T2, N0, potencial candidata a quimioterapia, Prueba genómica de recurrencia (OncoType Dx) Riesgo Bajo Riesgo Alto Inhibidor de aromatasa x24 semanas (+/- bloqueo ovariano) Quimioterapia neoadyuvante X18-24 semanas Cirugía
Notas del editor
- Main Points: The Oncotype DX® test was clinically validated to predict the risk of distant recurrence at 10 years in patients with ER-positive, node-negative breast cancer treated with tamoxifen. This was a prospectively designed trial using archived tumors from the NSABP B-14 trial The Recurrence Score® result was calculated for 668 patients: 51% of the patients fell into the low-risk group (n = 338), 22% fell into the intermediate-risk group (n = 149), and 27% fell into the high-risk group (n = 181) This graph demonstrates the difference in distant relapse-free survival (DRFS) over time for the different risk categories. The DRFS for the high- and low-risk groups were statistically significantly different; the 10-year DRFS for the low-risk category was 93% compared to 69% for the high-risk group Paik et al. N Engl J Med. 2004.
- Main Points: The study design and accrual are depicted here After eligibility verification and consent, study volunteers were preregistered and had a tumor specimen sent to be tested with the Oncotype DX Recurrence Score® test Upon receipt of results by the local site, subjects were then registered, with treatment assignment or randomization as shown 10,273 volunteers were registered between April 2006 and October 2010, resulting in 6711 evaluable subjects, or 65% randomized in the Recurrence Score® 11-25 group to receive endocrine therapy (ET) plus chemotherapy (the standard arm) or ET alone (the experimental arm) The remaining 35% were assigned to receive ET alone if the RS result was 0-10, or chemo plus ET if the Recurrence Score result was 26-100 Sparano et al. J Clin Oncol. 2008.
- Main Points: The primary analysis was performed after 836 iDFS events with a median follow-up of 7.5 years. This included 40.3% of all events with recurrence as the first event and 23.8% with distant recurrences as the first event For the primary endpoint of iDFS in the intent-to-treat cohort with Recurrence Score® 11-25 (Arms B and C): iDFS defined to be time from registration to first event, where the first event is any of the following: ipsilateral breast tumor recurrence, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary non-breast invasive cancer (excluding non-melanoma skin cancers), or death without evidence of recurrence In the intent-to-treat population, there was an approximately 1% difference in 9-year iDFS at 83.3% for Arm B and 84.3% for Arm C, demonstrating that endocrine therapy was non-inferior to chemotherapy plus endocrine therapy The hazard ratio was 1.08, and 95% confidence intervals were 0.94 and 1.24, not crossing the prespecified non-inferiority margin of 1.322, with a P value of 0.26, indicating that the primary trial endpoint of non-inferiority was met Results were similar for the as-treated population, as the non-inferiority margin likewise was not crossed Sparano et al. N Engl J Med. 2018.
- Main Points: The original B-20 trial showed that adding chemotherapy to tamoxifen resulted in an absolute benefit of 4.4% and was the basis for the recommendation that all women with ER-positive disease and tumors > 1cm be treated with hormone therapy plus chemotherapy. Nevertheless, it was not possible to discern which patients were benefitting from chemotherapy based on clinicopathologic factors The B-20 Breast Recurrence Score® test validation study was prospectively designed using archived tumor tissues from the original NSABP B-20 trial. Patients with a low Recurrence Score result did not benefit from chemotherapy, and patients with a high Recurrence Score result derived a large benefit (28% absolute benefit with a P value of < 0.001) from the addition of chemotherapy. A formal test of statistical interaction between the Recurrence Score as a continuous variable and chemotherapy treatment was performed and found to be significant (interaction P = 0.038) This was the first and only demonstration that a multi-gene assay could provide information regarding which patients would or would not benefit from the addition of chemotherapy to hormone therapy It was now possible to plan treatment for ER-positive patients based on the underlying biology of the tumor and personalize care and answer the question: Do I need chemotherapy? Paik et al. J Clin Oncol. 2006.
- Main Points: The original B-20 trial showed that adding chemotherapy to tamoxifen resulted in an absolute benefit of 4.4% and was the basis for the recommendation that all women with ER-positive disease and tumors > 1cm be treated with hormone therapy plus chemotherapy. Nevertheless, it was not possible to discern which patients were benefitting from chemotherapy based on clinicopathologic factors The B-20 Breast Recurrence Score® test validation study was prospectively designed using archived tumor tissues from the original NSABP B-20 trial. Patients with a low Recurrence Score result did not benefit from chemotherapy, and patients with a high Recurrence Score result derived a large benefit (28% absolute benefit with a P value of < 0.001) from the addition of chemotherapy. A formal test of statistical interaction between the Recurrence Score as a continuous variable and chemotherapy treatment was performed and found to be significant (interaction P = 0.038) This was the first and only demonstration that a multi-gene assay could provide information regarding which patients would or would not benefit from the addition of chemotherapy to hormone therapy It was now possible to plan treatment for ER-positive patients based on the underlying biology of the tumor and personalize care and answer the question: Do I need chemotherapy? Paik et al. J Clin Oncol. 2006.
- Main Points: The study design and accrual are depicted here After eligibility verification and consent, study volunteers were preregistered and had a tumor specimen sent to be tested with the Oncotype DX Recurrence Score® test Upon receipt of results by the local site, subjects were then registered, with treatment assignment or randomization as shown 10,273 volunteers were registered between April 2006 and October 2010, resulting in 6711 evaluable subjects, or 65% randomized in the Recurrence Score® 11-25 group to receive endocrine therapy (ET) plus chemotherapy (the standard arm) or ET alone (the experimental arm) The remaining 35% were assigned to receive ET alone if the RS result was 0-10, or chemo plus ET if the Recurrence Score result was 26-100 Sparano et al. J Clin Oncol. 2008.
- Main Points: When all Recurrence Score® (RS) result cohorts (0-10, 11-25, and 26-100) and treatment group assignments were considered, there were significant differences in the rates of distant recurrence (P < 0.001), driven largely by the higher likelihood of having an event in the cohort with an RS result of 26-100. Similar results were found for all other endpoints The 9-year rate of distant recurrence was very low for Arm A (RS 0-10; endocrine therapy alone) at 3% and the randomized Arms B & C (RS 11-25), which overlapped at 5%, indicating that patients with RS 0-25 can expect a low risk of distant recurrence on endocrine therapy only Patients in Arm D experienced a higher 9-year rate of distant recurrence at 13%, even though all patients received chemotherapy and endocrine therapy. Future trials focused on novel agents for adjuvant therapy should be focused on high-risk patients with RS 26-100 where better therapies are needed Distant recurrence was associated with the RS result as a continuous variable between 11 and 25, but there was no significant interaction between chemotherapy treatment and RS result in the RS 11-25 range Sparano et al. N Engl J Med. 2018.
- Main Points: When all Recurrence Score® (RS) result cohorts (0-10, 11-25, and 26-100) and treatment group assignments were considered, there were significant differences in the rates of distant recurrence (P < 0.001), driven largely by the higher likelihood of having an event in the cohort with an RS result of 26-100. Similar results were found for all other endpoints The 9-year rate of distant recurrence was very low for Arm A (RS 0-10; endocrine therapy alone) at 3% and the randomized Arms B & C (RS 11-25), which overlapped at 5%, indicating that patients with RS 0-25 can expect a low risk of distant recurrence on endocrine therapy only Patients in Arm D experienced a higher 9-year rate of distant recurrence at 13%, even though all patients received chemotherapy and endocrine therapy. Future trials focused on novel agents for adjuvant therapy should be focused on high-risk patients with RS 26-100 where better therapies are needed Distant recurrence was associated with the RS result as a continuous variable between 11 and 25, but there was no significant interaction between chemotherapy treatment and RS result in the RS 11-25 range Sparano et al. N Engl J Med. 2018.