Cómo seleccionar en la actualidad el mejor

tratamiento adyuvante en el CM RH+/HER2 - ?

DR OSCAR MAURICIO NIÑO GÓMEZ

ONCÓLOGO CLÍNICO
CLINICA UNIVERSITARIA COLOMBIA-CECIMIN
CLINICA DEL COUNTRY-LA COLINA
27 DE ENERO 2024
 CONFLICTOS DE INTERÉS

Speaker y Participación en Advisory board

• Bristol Myers Squibb, Novartis ,Merck Sharp and

Dohme, Biotoscana, Boehringer Ingelheim, Lilly, Roche,
Merck Serono
 NECESIDADES INSATISFECHAS : Estadios II y III

95% of patients diagnosed with breast cancer have early breast

cancer. Among these patients:
48% 34.6% 12.4% 5% There are nearly
3 times the number of
stage II patients vs stage III
patients at time of diagnosis
Stage I Stage II Stage III Stage IV

EBC ABC

Treatment in EBC is conducted with curative intent, but risk of recurrence remains a significant problem

27-37% of and 46-57% of stage III EBCs will recur

Iqbal J. JAMA2015. Pan H. NEJM 2017.

 AMPLIO ESPECTRO DE RECAÍDAS: DIFERENTE PRONÓSTICO

Tiempo a la recaída Recaídas tempranas en Ca de Mama= Enfermedad

3
agresiva
REGISTEM_GEICAM: 1st PFS and OS in ER+ MBC
with early relapse (<36m) vs late relapes (>120m)

> 50% de las recaídas ocurren después de los 5 años

Guerrero-Zotano A, ASCO 2023

Wangchinda P. World J Surg Oncol 2016.Guerrero-Zotano A. ASCO 2023.
¿COMO DEFINIMOS EL RIESGO DE RECAÍDA ?
 VARIABLES CLÍNICAS Y DE EXPRESIÓN GÉNICA

CLÍNICAS EXPRESIÓN GÉNICA

• Tamaño tumoral
• ONCOTYPE Dx RS
• Estado nodal
• MAMMAPRINT
• Grado, Ki 67
• Prosigna, EndoPredict
• Edad y estado menopáusico
• Breast Cancer Index

PREDECIR CORRECTAMENTE EL RIESGO

REQUIERE COMBINAR AMBAS VARIABLES, SOBRE
TODO EN RIESGO INTERMEDIO
Park YH. Ann Oncol 2011. Fasching PA. Breast Cancer Res Treat 2019.
TNM Y KI 67 IMPORTANTES FACTORES PRONÓSTICOS

DFS according to TNM stage DFS relative to Ki-67 and disease

stage categories

Disease-free survival
Stg II + Ki67 ≥20%
Stg III + Ki67 <10%

Stg III + Ki6710-19%

Stg III + Ki67 ≥20%

Time (years)

Park YH. Ann Oncol 2011. Fasching PA. Breast Cancer ResES2305158041
Treat 2019.
 ESTADIOS II Y III ALTO RIESGO DE RECIDIVA. EVIDENCIA EN
MUNDO REAL

• 41% de pacientes estadio II y 63%en estadio III

recaen en los primeros 10 años
2-Year Event Risk 3-Year Event Risk 5-Year Event Risk 10-Year Event
Population (95% CI), % (95% CI), % (95% CI), % Risk (95% CI), %
Overall
(N = 3133) 11.1 (10.1-12.3) 16.3 (15.0-17.7) 26.1 (24.5-27.9) 45.0 (42.7-47.3)

Stage II
9.4 (8.3-10.7) 13.8 (12.4-15.2) 22.7 (21.0-24.6) 40.5 (38.0-43.1)
(n = 2535)
Stage III
18.4 (15.5-21.8) 27.1 (23.6-31.0) 40.4 (36.2-44.9) 62.9 (57.9-67.9)
(n = 598)

O’Shaugnessy J. SABCS 2022.

¿CUÁL ES EL TRATAMIENTO ADYUVANTE
HOY DÍA ?
Algoritmo de tratamiento adyuvante en CM luminal

Bajo riesgo Riesgo Intermedio Alto riesgo

Plataforma Genómica
QUIMIOTERAPIA
HT x 5 años PRE: HT + SFO
POST: HT Extendida

Bajo riesgo genómico Alto riesgo genómico

Riesgo Intermedio POSTMenopausica Riesgo Intermedio PREmenopausia

QUIMIOTERAPIA
HT x 5 años PRE: HT + SFO
POST: HT Extendida

Kino Gavilá , IVO Agosto 2023

 BENEFICIO DE SFO EN PTES PREMENOPÁUSICA

Recurrence in ER+ BC by nodal status OFS vs not Breast Cancer Mortality

Slide 13

Slide13

Gray R..ASCO 2023

BENEFICIO DE HT PROLONGADA

Burstein H, et al, J Clin Oncol 2021. Arnedos M, ESMO 2021. Del Maestro , ESMO 2021.
Calculadora beneficio HT prolongada adyuvante

https://www.cts5-calculator.com/about
ROL DE LOS INHIBIDORES CDK4/6 EN EL
TRATAMIENTO ADYUVANTE
Estudios con Inhibidores de CDK 4/6 en contexto adyuvante

Start date: Start date: Start date: Start date:

November 2013 August 2015 July 2017 December 2018

PENELOPE-B1 PALLAS2 monarchE3 NATALEE4,5

N 1250 5796 5637 5101
Sex Women Men and women Men and women Men and women
Menopausal Pre- and Pre- and Pre- and postmenopausal
Pre- and postmenopausal
status postmenopausal postmenopausal
Disease severity CPS-EG ≥3, or 2 with Intermediate (stage II) • Cohort 1: ≥4 ALN or 1-3 ALN with at Anatomical Stage Group
post-neoadjuvant and high-risk (stage III) least: tumor size ≥5 cm or grade 3 (according to AJCC 8th
therapy pathological • Limit of 1000 • Cohort 2: 1-3 ALN + Ki-67 ≥20%; no edition): intermediate
node-positive stage IIA patients grade 3, no tumor size ≥5 cm (stage II) and high-risk
(stage III)a
CDK4/6i, dose PAL 125 mg QD PAL 125 mg QD RIB 400 mg QD
(3 weeks on/1 week off) (3 weeks on/1 week off) ABE 150 mg BID (3 weeks on/1 week off)
ET partner Standard adjuvant ET
(eg, AI, TAM ± LHRH AI or TAM ± LHRH Standard adjuvant ET LET or ANA (± LHRH
agonist (eg, AI, TAM, ± LHRH agonist) agonist)
agonist)
Duration of
~13 months 2 years Up to 2 years 3 years
CDK4/6i therapy

û û ü ü
Significant iDFS
benefit

Slamon Dl. ASCO 2023.. Mayer E. Lancet Oncol 2021. Loibl S. J Clin Oncol. 2021. Johnston S, et al. J Clin Oncol.
Estudio MONARCH-E: Diseño del Estudio

S Johnston. J Clin Oncol 2020. N Harbeck. Ann Oncol 2021. S Johnston. Lancet Oncol 2022.
Estudio MONARCH-E: Características Basales
Abemaciclib + ET ET Alone
N=2808, n (%) N=2829, n (%)
Age Median (range) 51 (23-89) 51 (22-86)
Age categories <65 years 2371 (84.4) 2416 (85.4)
≥65 years 437 (15.6) 413 (14.6)
Gender Female 2787 (99.3) 2814 (99.5)
Male 21 (0.7) 15 (0.5)
Regiona North America/Europe 1470 (52.4) 1479 (52.3)
Asia 574 (20.4) 582 (20.6)
Other 764 (27.2) 768 (27.1)
Menopausal Statusa Premenopausal 1221 (43.5) 1232 (43.5)
Postmenopausal 1587 (56.5) 1597 (56.5)
Prior Treatmenta Neoadjuvant chemotherapy 1039 (37.0) 1048 (37.0)
Adjuvant chemotherapy 1642 (58.5) 1647 (58.2)
No chemotherapy 127 (4.5) 134 (4.7)
Baseline ECOG PS 0 2405 (85.7) 2369 (83.8)
1 401 (14.3) 455 (16.1)

S Johnston. J Clin Oncol 2020.

 Estudio MONARCH-E: Características Basales
Abemaciclib + ET ET alone
Category1
N=2808, n (%) N=2829, n (%)
Number of Positive 0 7 (0.2) 7 (0.2)
Lymph Nodes
1-3 1119 (39.9) 1143 (40.4) Additional high-risk eligibility Abemaciclib + ET ET Alone
≥4 1680 (59.8) 1679 (59.3) criteria for patients with 1-3 nodes2 N=2808, n (%) N=2829, n (%)

Histological Grade Grade 1 209 (7.4) 215 (7.6)

Tumor Size ≥5 cm (pathology)a 249 (8.9) 236 (8.3)
Grade 2 1373 (48.9) 1395 (49.3)
Grade 3 1090 (38.8) 1066 (37.7)
Primary Tumor Size <20 mm 780 (27.8) 765 (27.0) Tumor Size ≥5 cm (imaging)a, b 152 (5.4) 158 (5.6)
by Pathology
Following Definitive 20 - 50 mm 1369 (48.8) 1419 (50.2)
Surgery
≥50 mm 610 (21.7) 612 (21.6) Histologic Grade 3a 629 (22.4) 618 (21.8)

Central Ki-67 <20% 953 (33.9) 973 (34.4)

Central Ki-67 ≥20% Onlyc 216 (7.7) 237 (8.4)
≥20% 1262 (44.9) 1233 (43.6)
Unavailable 593 (21.1) 623 (22.0)
Progesterone Positive 2421 (86.2) 2453 (86.7)
Receptor Status
Negative 298 (10.6) 294 (10.4)

S Johnston. J Clin Oncol 2020.

Estudio MONARCH-E: Características Basales

Administration of Adjuvant Endocrine Therapy

S Johnston. J Clin Oncol 2020.

Estudio MONARCH-E: Ki67 Cohorte 1 es pronóstico no predictivo

Cohort 1*
C1 Ki-67 High C1 Ki-67 Low
Abemacicli ET Abemacicli ET
b + ET alone b + ET alone
N=1017 N=986 N=946 N=968
IDFS
Number of
147 224 91 141
events, n
HR (95% CI) 0.618 (0.501, 0.762) 0.624 (0.478, 0.814)
DRFS
Number of
126 193 74 119
events, n
HR (95% CI) 0.612 (0.488, 0.767) 0.613 (0.458, 0.821)
OS (Immature)
Number of
68 88 39 50
events, n
HR (95% CI) 0.733 (0.533, 1.007) 0.772 (0.506, 1.175)

*Ki-67 value was missing in 1203 (23.5%) patients

Within Cohort 1, similar abemaciclib treatment effects were observed regardless of Ki-67 index

S Johnston. SABCS 2022.

 Estudio MONARCH-E: Seguridad

Adverse Events (safety population)1

Abemaciclib + ET ET alone
≥40% in either arm
N=2791, n (%) N=2800, n (%)
Any grade Grade ≥ 3 Any grade Grade ≥ 3
Any adverse event 2745 (98.4%) 1388 (49.7) 2486 (88.8%) 456 (16.3)
Diarrhea 2331 (83.5%) 219 (7.8)a 242 (8.6%) 6 (0.2)
Infectionsb 1429 (51.2%) 155 (5.6) 1102 (39.4%) 83 (3.0)c
Neutropenia 1278 (45.8%) 546 (19.6) 157 (5.6%) 23 (0.8)
Fatigue 1133 (40.6%) 80 (2.9) 499 (17.8%) 4 (0.1)
Additional adverse events of interest
Venous thromboembolic eventd 71 (2.5%) 38 (1.4%)e 17 (0.6%) 8 (0.3%)
Pulmonary embolismf 28 (1.0%) 28 (1.0%) 4 (0.1%) 4 (0.1%)
Interstitial lung diseaseg 89 (3.2%) 11 (0.4%) 37 (1.3%) 1 (0.0%)

• Safety results for abemaciclib in EBC are consistent with the known safety profile in ABC3
• Diarrhea was the most frequent AE in patients with HR+/HER2− EBC treated with abemaciclib + ET1
• Overall, 16.6% of patients in the abemaciclib arm discontinued abemaciclib, and 66.0% of patients who discontinued
abemaciclib remained on ET2

S Johnston. Lancet Oncol 2022.

NATALEE study design1,2

Slamon D. ASCO 2023.

 Estudio NATALEE vs MONARCH-E: Criterios Inclusión

AJCC
Anatomical TN (M0) NATALEE2 monarchE3
Staging1
Stage IIA T0N1 Only if grade 3 or Ki-67 ≥20%
T1N1 Only if grade 3 or Ki-67 ≥20%

T2N0 Only if G3; or G2 with Ki-67 ≥20% or high genomic riska

Stage IIB T2N1 Only if grade 3 or Ki-67 ≥20%

T3N0
Stage IIIA T0N2
T1N2
T2N2
T3N1
T3N2
Stage IIIB T4N0
Only if tumor size ≥5 cm or
T4N1
grade 3 or Ki-67 ≥20%
T4N2
Stage IIIC Any TN3
NATALEE allowed: monarchE allowed:
• Any N1, N2, N3 • Any N2, N3
• N0: T2 [(G2 + high genomic risk or Ki-67≥ 20%) or G3)], T3, T4 • N1 only if G3 or tumor size ≥ 5cm or Ki-67≥20%

Slamon D. ASCO 2023. Johnston S. Lancet Oncol 2022.

 8

Baseline characteristics
RIB + NSAI NSAI Alone All Patients
Parameter
n = 2549 n = 2552 N = 5101
Age, median (min-max), years 52 (24-90) 52 (24-89) 52 (24-90)
Menopausal status, n (%)
Mena and premenopausal women 1126 (44) 1132 (44) 2258 (44)
Postmenopausal women 1423 (56) 1420 (56) 2843 (56)
Anatomical stage,b,c n (%)
Stage IIA 479 (19) 521 (20) 1000 (20)
Stage IIB 532 (21) 513 (20) 1045 (20)
Stage III 1528 (60) 1512 (59) 3040 (60)
Nodal status at diagnosis, n (%)
NX 272 (11) 264 (10) 536 (11)
N0 694 (27) 737 (29) 1431 (28)
N1 1050 (41) 1049 (41) 2099 (41)
N2/N3 483 (19) 467 (18) 950 (19)
Prior ET, n (%)d
Yes 1824 (72) 1801 (71) 3625 (71)
Prior (neo)adjuvant CT, n (%)
Yes 2249 (88) 2245 (88) 4494 (88)
ECOG PS, n (%)
0 2106 (83) 2132 (84) 4238 (83)
1 440 (17) 418 (16) 858 (17)
CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; ET, endocrine therapy; N0, no nodal involvement; N1, 1-3 axillary lymph nodes; N2, 4-9 axillary lymph nodes; N3, ≥ 10 axillary lymph nodes or infra- or supraclavicular lymph nodes; NSAI,
nonsteroidal aromatase inhibitor; NX, regional nodes were not assessed; OFS, ovarian function suppression; RIB, ribociclib.
a In the RIB + NSAI arm, there were 11 men (0.4%); in the NSAI alone arm, there were 9 men (0.4%). b A total of 14 patients with stage I disease were included: 9 (0.4%) in the RIB + NSAI arm and 5 (0.2%) in the NSAI alone arm. c Stage is derived using TNM from surgery for patients

having not received (neo)adjuvant treatment or as worst stage derived using TNM at diagnosis and TNM from surgery for patients having received (neo)adjuvant treatment. d Prior OFS was received by 670 patients (26.3%) in the RIB + NSAI arm and 620 (24.3%) in the NSAI alone arm.

PRESENTED BY: Dennis Slamon MD, PhD

ES2306039784

Slamon D. ASCO 2023.

Favorable safety profile with ribociclib 400 mg vs 600 mg<br /><br />

Slamon D. ASCO 2023.

 Conclusiones
• El tratamiento adyuvante en CM luminal continúa siendo una
necesidad insatisfecha
• Tasas de recaída entre 40-60% para estadio II-III
• Tras 5 años de seguimiento: Abemaciclib demuestra beneficio
sostenido en iDFS y DDFS
• Ribociclib en estudio NATALEE logra beneficio en iDFS y DDFS tras
33 meses de seguimiento (20% de ptes aún en tratamiento)
• Necesidad de perfilar a las pacientes de mayor riesgo que se
puedan beneficiar … a día de hoy