#seom2018* - seom: sociedad espa · t3 n1 m0 iiia t3 n2 m0 iiia t4 n0 m0 iiib t4 n1 m0 iiib t4 n2...

#SEOM2018

#SEOM2018

Disclosure Informa0on

q  Employment: HOSPITAL UNIVERSITARIO DONOSTIA- OSAKIDETZA (Servicio Vasco de Salud)

q  Consultant or Advisory Role: AstraZeneca, Pfizer, Novartis, Roche, Palex

q  Stock Ownership:No

q  Research Funding: AstraZeneca, Pfizer, Novartis, Roche

q  Speaking: AstraZeneca, Pfizer, Novartis, Roche, Eisai

q  Grant support: No

q  Other: Meetting travel expenses: AstraZeneca, Pfizer, Roche

#SEOM2018 3

N Engl J Med 2016; 375:711-‐713

Uncertainty is a very good thing: it's the beginning of an inves0ga0on, and the inves0ga0on should never end. Tim Crouch (experimental theatre maker) Medicine is a science of uncertainty and an art of probability. William Osler (Canadian physician)

#SEOM2018

¿Qué es “precoz” y “muy luminal”?

4 h[ps://www.cancer.gov/publica0ons/dic0onaries/cancer-‐terms/def/early-‐stage-‐breast-‐cancer

#SEOM2018

TNM 8ª edicion (UICC, AJCC)

5

48. Breast

AJCC Cancer Staging Manual, Eighth Edition © The American College of Surgeons (ACS), Chicago, Illinois. Content is available for user’s personal use.It cannot be sold, distributed, published, or incorporated into any software, product, or publication without a written license agreement with ACS. The content cannot be modified, changed, or updated without the express written permission of ACS. All Rights Reserved. Last updated 9-Nov-17 Page 73 of 96

When T is… And N is… And M is… Then the stage group is… Tis N0 M0 0

T1 N0 M0 IA

T0 N1mi M0 IB

T1 N1mi M0 IB

T0 N1 M0 IIA

T1 N1 M0 IIA

T2 N0 M0 IIA

T2 N1 M0 IIB

T3 N0 M0 IIB

T0 N2 M0 IIIA

T1 N2 M0 IIIA

T2 N2 M0 IIIA

T3 N1 M0 IIIA

T3 N2 M0 IIIA

T4 N0 M0 IIIB

T4 N1 M0 IIIB

T4 N2 M0 IIIB

Any T N3 M0 IIIC

Any T Any N M1 IV

Notes: 1. T1 includes T1mi. 2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB. 3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. The designation pM0 is not valid; any M0 is clinical. 6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is Stage

IV and remains Stage IV regardless of response to neoadjuvant therapy. 7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant

metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.

8. Staging following neoadjuvant therapy is denoted with a “yc” or “yp” prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

FOR PERSONAL U

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48. Breast


When T is… And N is… And M is… Then the stage group is… Tis N0 M0 0

T1 N0 M0 IA

T0 N1mi M0 IB

T1 N1mi M0 IB

T0 N1 M0 IIA

T1 N1 M0 IIA

T2 N0 M0 IIA

T2 N1 M0 IIB

T3 N0 M0 IIB

T0 N2 M0 IIIA

T1 N2 M0 IIIA

T2 N2 M0 IIIA

T3 N1 M0 IIIA

T3 N2 M0 IIIA

T4 N0 M0 IIIB

T4 N1 M0 IIIB

T4 N2 M0 IIIB

Any T N3 M0 IIIC

Any T Any N M1 IV

Notes: 1. T1 includes T1mi. 2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB. 3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. The designation pM0 is not valid; any M0 is clinical. 6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is Stage

IV and remains Stage IV regardless of response to neoadjuvant therapy. 7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant

metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.

8. Staging following neoadjuvant therapy is denoted with a “yc” or “yp” prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

FOR PERSONAL U

SE ONLY

AJCC Cancer Staging Manual, Eighth Edi0on © The American College of Surgeons (ACS), Chicago, Illinois. UICC 8th edi0on. 2017. Wiley Blackwell. Published 2017 John Wiley&Sons, Ltd.

AJCC Estadiaje Pronós:co Incluye Grado HER2 RH: RE y RP RS-‐ Oncotype DX -‐  T1-‐2N0M0, G1-‐3,

HER2(-‐), RE+, RP+/-‐, RS< 11 = > IA

Precoz Estadios I-‐II +/-‐ III (¿?)

#SEOM2018


6

48. Breast

AJCC Cancer Staging Manual, Eighth Edition © The American College of Surgeons (ACS), Chicago, Illinois. Content is available for user’s personal use.It cannot be sold, distributed, published, or incorporated into any software, product, or publication without a written license agreement with ACS. The content cannot be modified, changed, or updated without the express written permission of ACS. All Rights Reserved. Last updated 9-Nov-17 9 of 96

T Category T Criteria T1c Tumor > 10 mm but ≤ 20 mm in greatest dimension T2 Tumor > 20 mm but ≤ 50 mm in greatest dimension T3 Tumor > 50 mm in greatest dimension T4 Tumor of any size with direct extension to the chest wall and/or to the skin

(ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b are present T4d Inflammatory carcinoma (see “Rules for Classification”) * Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition.

Definition of Regional Lymph Nodes – Clinical (cN) cN Category cN Criteria cNX* Regional lymph nodes cannot be assessed (e.g., previously removed) cN0 No regional lymph node metastases (by imaging or clinical examination) cN1 Metastases to movable ipsilateral Level I, II axillary lymph node(s) cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger

than 2.0 mm) cN2 Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or

matted; or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN2a Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures

cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN3 Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without FOR PERSONAL U

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48. Breast


T Category T Criteria T1c Tumor > 10 mm but ≤ 20 mm in greatest dimension T2 Tumor > 20 mm but ≤ 50 mm in greatest dimension T3 Tumor > 50 mm in greatest dimension T4 Tumor of any size with direct extension to the chest wall and/or to the skin

(ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b are present T4d Inflammatory carcinoma (see “Rules for Classification”) * Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition.

Definition of Regional Lymph Nodes – Clinical (cN) cN Category cN Criteria cNX* Regional lymph nodes cannot be assessed (e.g., previously removed) cN0 No regional lymph node metastases (by imaging or clinical examination) cN1 Metastases to movable ipsilateral Level I, II axillary lymph node(s) cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger

than 2.0 mm) cN2 Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or

matted; or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN2a Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures

cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN3 Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without FOR PERSONAL U

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#SEOM2018

Perou et al Nature 406, 747-‐752 Sorlie T et al PNAS 2001 TCGA. Nature 2012; Ades F JCO 2014

Sub0pos intrínsecos – expresión génica – RE + – sub0po Luminal (A y B)

7

é Expresión de genes regulados por el RE

Luminal A vs B – alteraciones genómicas diferenciales

Luminal B vs A •  ê expresión de genes regulados por RE •  ê expresión del RP •  é grado tumoral •  éexpresión de genes relacionados con la proliferación •  Ac0vación de vias GFR (IGF-‐1,R, PI3K/AKT/MTOR

#SEOM2018

Grupo intrínseco – Luminal A vs Luminal B

8

Parker Js JCO 2009 Ades F JCO 2014 Kwa M Nat Rev Clin Oncol 2017 Curigliano G. Ann Onc 2017

Subgrupo Intrinseco – PAM 50 Luminal -‐ like Otras plataformas genómicas -‐  Oncotype DX – Low risk (<11, <25?) -‐  Mammaprint – RH+/HER2-‐ Low risk -‐  EndoPredict – low risk

AP H&E + Inmunohistoquimia

Luminal A-‐ like -‐  Alta expresion de RE (> 50-‐ 80%, Allred >6 -‐  RP > 20% -‐  Ki 67 bajo (<14%, < 20%) -‐  Grado 1-‐2 -‐  Bajo riesgo “molecular”

<

#SEOM2018


9

48. Breast


TABLE 48.2. Clinically Defined Subtypes of Breast Cancer. Modified with permission from Konecny et al. 200388 and Eiermann et al. 2013.94

Clinically Defined – Treatment Oriented Subtypes of Breast Cancer LUMINAL LIKE

Hormone receptor-positive and HER2-negative luminal disease as a spectrum:

LUMINAL LIKE Hormone receptor-positive and HER2-negative luminal disease as a spectrum:

(Luminal A-like) High receptor, low proliferation

Multiparameter molecular marker “favorable prognosis,” if available; high ER/PR and clearly low proliferation rate (low Ki-67, low mitotic count); generally histological grade 1 or 2

(Luminal B-like) Low receptor, high proliferation

Multiparameter molecular marker “unfavorable prognosis,” if available; lower ER/PR with high proliferation rate (high Ki-67, high mitotic count); generally histological grade 3

HER2 LIKE HER2-positive

HER2-positive and hormone receptor-negative or HER2-positive and hormone receptor-positive; generally histological grade 3

BASAL LIKE Triple-negative

Negative ER, PR, and HER2; generally histological grade 3

Luminal A-type tumors are usually low-grade invasive ductal carcinomas (NOS type) or special types of carcinoma—such as tubular, cribriform, or mucinous—and have an excellent prognosis. These tumors generally have a poor response to traditional chemotherapy but have an excellent response to endocrine therapies. Luminal B tumors tend to be poorly differentiated, less likely to respond to endocrine therapy and more likely to respond to traditional chemotherapy. The HER2-like (or HER2-enriched) tumors, prior to the introduction of anti-HER2 therapy, were the most aggressive subtype and had the highest mortality rate and shortest survival. However, in current practice, when appropriately managed with anti-HER2 therapy, patients with these tumors have a much better prognosis. The basal-like tumors, which are thought to arise from myoepithelial cells, have the highest mortality and are most difficult to treat with adjuvant therapy.

Multigene Panels, Genomic Profiles, Signature Scores Another consideration for adding biologic factors into breast cancer staging is to incorporate the findings from multigene panel testing. The multigene panels test for the levels of expression of multiple genes in the breast cancer tissue, most often by some measure of the levels of message (RNA) present in the tumor. Several such panels are in clinical use because of studies demonstrating their value in providing more specific prognostic information and in predicting sensitivity to classes of systemic agents, especially chemotherapy.

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AJCC Cancer Staging Manual, Eighth Edi5on © The American College of Surgeons (ACS), Chicago, Illinois.

#SEOM2018

¿Qué es “precoz” y “muy luminal”?

10

TNM clínico I-‐II +/-‐IIIA

Luminal A/A-‐Like

#SEOM2018

Posibles ventajas del tratamiento neoadyuvante

•  Facilitar cirugías menos agresivas –  Conservación de la mama (CS) –  No linfadenectomía en N+ (cN+à pN0)

•  Test “in vivo” del efecto del tratamiento –  Tratamiento posterior adaptado a la respuesta? –  Inves0gación

•  Biomarcadores de respuesta y resistencia •  Nuevos fármacos •  Ensayos de adaptación terapéu0ca según respuesta •  Aprobación precoz de terapias eficaces (FDA, ¿?)

•  Riesgo de mutación patogénica – Ca hereditario-‐ Hacer tratamiento a la espera de resultado – planificación de la cirugía posterior

11

#SEOM2018

Posibles desventajas del tratamiento neoadyuvante

•  Decisión de tratamiento sin tener toda la información necesaria (pTNM)

•  Retraso innecesario de la cirugía •  Sobretratamiento •  Infratratamiento •  Progresión durante el tratamiento neoadyuvante

12

#SEOM2018

¿Qué 0po de tratamiento neoadyuvante (NA)?

•  Quimioterapia (NAQT) •  Hormonoterapia (NAH) – Larga (> 3-‐4m) – Perioperatoria – 2-‐4 semanas

13

#SEOM2018

NAQT -‐ LumA •  QT neo = QT post en términos de SV •  Respuesta patológica – pCR ypT0-‐isN0 – % pCR bajo – Lum-‐A 5-‐9%. (G1-‐2 German trials 8,9%, Metaanálisis 7,5% vs G3 15,4% y 16%, Prat et al-‐ PAM50 – LumA 6%, LumB 16%)

– pCR vs no PCR – no discriminación pronós0ca

14

HR=0.49, P* < 0.001 HR=0.63, P* = 0.07 HR=0.27, P* < 0.001

Cortazar P, et al. Lancet 2014;384:164-172

Von Minckwitz et al. JCO 2012 Cortazar P.Lancet 2004 Prat A. BMC md 2015

#SEOM2018

NAQT -‐ LumA (2)

•  Aumenta el % de candidatas a CS?-‐ SI-‐ 50%

•  Disminuye el nº de linfadenectomías en N+ ? –  NO (bajo% pCR, alta tasa FN)

•  Necesitan todas las pacientes con tumores Luminales A QT adyuvante? –  NO –  Estudios en adyuvancia – Oncotype DX -‐ T1-‐T2 N0 RS <25 (TaylorX), y prob N1-‐3 tampoco (pte estudio RxPONDER), Mammaprint (Mindact)

15 Enokido K. CBC 2016; Cardoso F NEJM 2016; Sparano JA NEJM 2015; Sparano JA NEJM 2018

n engl j med nejm.org 7

21-Gene Expression Assay in Breast Cancer

S12 and S13 in the Supplementary Appendix) but not for freedom of recurrence of breast cancer at a distant site or distant or local–regional site. In women 50 years of age or younger, chemotherapy was associated with a lower rate of distant recur-rence than endocrine therapy if the recurrence score was 16 to 20 (percentage-point difference, 0.8 at 5 years and 1.6 at 9 years) or 21 to 25 (per-

centage-point difference, 3.2 at 5 years and 6.5 at 9 years), although the rates of overall survival were similar (Table 3). Conversely, in the 40% of women 50 years of age or younger who had a re-currence score of 0 to 15, the rate of distant re-currence was approximately 2% at 9 years among those who had been assigned (either randomly or nonrandomly) to endocrine therapy alone.

Figure 2. Clinical Outcomes among Patients with a Recurrence Score of 11 to 25.

Kaplan–Meier estimates of survival rates in the analysis according to the assigned treatment group are shown for the group that received endocrine therapy alone and the group that received chemoendocrine therapy in the inten-tion-to-treat analysis of invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death) and freedom from recurrence of breast cancer at a distant site. The hazard ratios are for the endocrine-therapy group versus the chemoendocrine-therapy group.

B Freedom from Recurrence at a Distant Site

A Invasive Disease–free Survival

1.0

1.0

Prob

abili

ty o

f Inv

asiv

eD

isea

se–f

ree

Surv

ival

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.00 24 36 48 84 108

Months

Hazard ratio for invasive-disease recurrence, second primary cancer,or death, 1.08 (95% CI, 0.94–1.24)

P=0.26

No. at RiskChemoendocrine therapyEndocrine therapy

33123399

31043194

12

32043293

29933081

28492953

60

26452741

17811859

72

23352431

96

11301197

523537

Prob

abili

ty o

f Fre

edom

from

Recu

rren

ce a

t a D

ista

nt S

ite

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.00 24 36 48 84 108

Months

Hazard ratio for recurrence at a distant site, 1.10 (95% CI, 0.85–1.41)P=0.48

No. at RiskChemoendocrine therapyEndocrine therapy

33123399

31423239

12

32153318

30593147

29353033

60

27342833

18661947

72

24322537

96

11971267

554581

Endocrine therapy Chemoendocrine therapy

The New England Journal of Medicine Downloaded from nejm.org at OSAKIDETZA/SVS/DIRECCION GRAL on June 7, 2018. For personal use only. No other uses without permission.

Copyright © 2018 Massachusetts Medical Society. All rights reserved.

n engl j med nejm.org 6

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

cancer of the opposite breast in 15, other inva-sive new primary cancer in 43, and death with-out another event in 12. The Kaplan–Meier esti-mates for each end point examined are shown in Figure 1.

In this cohort, the rate of invasive disease–free survival at 5 years was 93.8% (95% CI, 92.4 to 94.9). The rate of freedom from recurrence of breast cancer at a distant site at 5 years was

99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence at 5 years was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival at 5 years was 98.0% (95% CI, 97.1 to 98.6).

Multivariate Analysis and Effect of Tumor Grade and Age of the Patient

In a multivariate analysis that included age (≤50 years vs. 51 to 60 years vs. 61 to 75 years), tumor

Figure 1. Kaplan–Meier Estimates in the Analyses of Invasive Disease–free Survival, Freedom from Recurrence of Breast Cancer at a Distant Site, Freedom from Recurrence at Any Site, and Overall Survival.

A total of 1626 patients with a recurrence score of 0 to 10 (on a scale from 0 to 100, with higher scores indicating a greater risk of recur-rence) were included in the analyses. In the time-to-event analysis of invasive disease–free survival, Panel A shows the probability of freedom from the first event of recurrence of ipsilateral breast tumor, local recurrence, regional recurrence, distant recurrence, contralat-eral second primary invasive cancer, second primary nonbreast invasive cancer (excluding nonmelanoma skin cancer), or death without evidence of recurrence (which corresponds to the standardized definitions for efficacy end points [STEEP]23 definition of invasive dis-ease–free survival). In the time-to-event analysis of freedom from the recurrence of breast cancer at a distant site, Panel B shows the probability of freedom from the first event of distant recurrence of breast cancer or death with distant recurrence, if death was the first manifestation of distant recurrence (which corresponds to the STEEP definition of distant recurrence–free interval). In the time-to-event analysis of freedom from recurrence at any site, Panel C shows the probability of freedom from the first event of recurrence of breast cancer (ipsilateral breast cancer, local or regional recurrence, or distant recurrence) or the date of death with recurrence, if death was the first manifestation of recurrence (which corresponds to the STEEP definition of recurrence-free interval). Panel D shows the proba-bility of overall survival in the time-to-event analysis. In each panel, dashed lines indicate 95% confidence intervals and the insets show the same data on an enlarged y axis.

Prob

abili

ty o

f Dis

ease

-free

Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36 48 60

Months

A Invasive Disease–free Survival

Prob

abili

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f Fre

edom

from

Eve

nt

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36 48 60

Months

B Freedom from Recurrence of Breast Cancer at Distant Site

Prob

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f Fre

edom

from

Eve

nt

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36 48 60

Months

C Freedom from Recurrence at Any Site

Prob

abili

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f Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36 48 60

Months

D Overall Survival

1.00

0.95

0.90

0.85

0.80

0.000 12 24 36 48 60

1.00

0.95

0.90

0.85

0.80

0.000 12 24 36 48 60

1.00

0.95

0.90

0.85

0.80

0.000 12 24 36 48 60

1.00

0.95

0.90

0.85

0.80

0.000 12 24 36 48 60

The New England Journal of Medicine Downloaded from nejm.org at OSAKIDETZA/SVS/DIRECCION GRAL on September 30, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

RS <11

RS 11-‐25

N0-‐ RS -‐ TaylorX

#SEOM2018

NAQT -‐ LumA (3)

Respuesta a Qt cambia la ac0tud posterior? •  HT adyuvante en todos los casos •  Mas QT si enfermedad residual? – La pCR no es claro factor pronós0co – Create –X Capecitabina – Beneficio a expensas de TN (HR+ : DFS 76.4% vs 73.4% (HR 0.81; 95% CI, 0.55 to 1.17), OS 93.4% versus 90.0% (HR 0.73; 95% CI, 0.38 to 1.40)

16 Masuda N. NEJM 2017

#SEOM2018

NAH – Luminal A •  La HT es el [o adyuvante estándar en CM RH+ hagan QT

previa o no •  Aumenta el % de candidatas a CS?-‐ SI-‐ 50% •  Disminuye el nº de linfadenectomías en N+ ?

–  Prob NO (bajo% pCR, no estudios específicos para pacientes tratadas con NAH N+ estudio de GC post)

17 Spring L JAMA ONCOL 2016 Grossman J Surg Oncol Clin N Am 2018

Table 2Neoadjuvante endocrine therapy versus neoadjuvant chemotherapy trials

Source (TrialName) No.

Patient Characteristics atBaseline Chemotherapy Endocrine Therapy Primary Endpoint

Response(per PrimaryEndpoint)

Rate of BreastCancer Surgery

Semiglazovet al,11 2007

239 Postmenopausal ER1 and/or PR1, stages IIA to IIIB

Doxorubicin 1 paclitaxel !4 cycles

Anastrozole orexemestane!12 wk

CR by palpation 64% CTvs64% ET

24% CTvs33% ET

Alba et al,12

2012 (GEICAM/2006–03)

95 51% premenopausalER1/PR1/HER2"/cytokeratin 8/181

EC ! 4 cycles, followed bydocetaxel ! 4 cycles

Exemestane (1goserelin ifpremenopausal)! 24 wk

OR by RECISTcriteria, MRI

66% CTvs48% ET

47% CTvs56% ET

Palmieri et al,13

2014 (NEOCENT)44 Postmenopausal ER1 5-fluorouracil 1 EC !6

cycles, switched todocetaxel after 3 cycles ifstable disease orprogressive disease

Letrozole !18 wk OR by ultrasound,mammography

55% CTvs59% ET

55%CTVs68% ET

Abbreviations: CR, clinical response; CT, chemotherapy; EC, epirubicin 1 cyclophosphamide; ET, endocrine therapy; OR, objective response.

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ireccion General

Osakidetza. A

RAB from

ClinicalKey.com

by Elsevier on April 05, 2018. For personal use only. N

o other uses without perm

ission. Copyright ©

2018. Elsevier Inc. All rights reserved.

#SEOM2018

NAH – Luminal A (2)

•  Respuesta patológica – pCR ypT0-‐isN0 – % pCR bajo (<10%)

•  Otros marcadores de respuesta – Marcadores de repuesta precoces

•  Ki 67 – descenso tras 2-‐4 semanas de tratamiento

– PEPI score – Otros cambios moleculares (firmas genómicas…)

18

Spring L JAMA ONCOL 2016 Grossman J Surg Oncol Clin N Am 2018

#SEOM2018 19


JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E

Avoidance of Negative Results inAdjuvant Endocrine Therapy Trials forEstrogen Receptor–Positive BreastCancer

TO THE EDITOR: On the basis of studies that demonstrate thatletrozole can suppress plasma estradiol levels to a greater extentthan anastrozole,1 the adjuvant activity of these endocrine agentswere compared in 4,136 patients with node-positive breast cancerin the Letrozole (Femara) Versus Anastrozole Clinical Evaluation(FACE) trial. In their article in Journal of Clinical Oncology, Smithet al2 reported equivalent efficacy. Alternative or additional phar-macodynamic markers for comparing the efficacy adjuvant en-docrine agents might have avoided the unrealized investmentand disappointment of a negative trial.

One promising option is to study the tumor proliferationmarker protein encoded by the MKI67 gene (Ki-67) before andafter the initiation of neoadjuvant or presurgical endocrinetherapy. After starting neoadjuvant endocrine therapy, thedegree of Ki-67 positivity has reproducible prognostic andpredictive value both in terms of individual outcomes,3 and interms of identifying the relative efficacy of various adjuvantendocrine approaches.4 Before the results of the FACE trial,three adjuvant endocrine therapy trials (BIG [Breast Interna-tional Group] 1-98, ATAC [Arimidex, Tamoxifen, Alone or inCombination], and MA27) could be matched to three neo-adjuvant studies with the same treatment randomization (P024,Immediate Preoperative Anastrozole, Tamoxifen, or Combinedwith Tamoxifen [IMPACT], and American College of SurgeonsOncology Group [ACOSOG] Z1031).4 In each case, the degreeof Ki-67 suppression in the neoadjuvant study paralleled theresult of the adjuvant study. In the case of P024 and IMPACT,Ki-67 suppression was greater for letrozole than for tamoxifenor anastrozole versus tamoxifen, which accurately predicted that

BIG 1-98 and ATAC would both be positive in favor of thearomatase inhibitor. Ki-67 data from IMPACT also indicatedthat the combination of tamoxifen and anastrozole would notbe more effective than tamoxifen alone, which suggests that theneoadjuvant endocrine therapy model could also provide valu-able negative predictive information to prevent futile compari-sons between endocrine approaches in the adjuvant setting.5 Thisproposition was further supported when the ACOSOG Z1031Ki-67 analysis predicted that exemestane would be equivalent toanastrozole,6 the final result in the MA27 study.7 The new clinicaldata from the FACE trial again demonstrate that Ki-67 sup-pression data can reliably identify futile comparisons betweenendocrine agents because no differences were found betweenletrozole and anastrozole in the ACOSOG Z1031 comparison(Table 1). Although the POETIC (Perioperative Endocrine Ther-apy for Individualizing Care) trial, a presurgical Ki-67 suppres-sion study that compared anastrozole and letrozole in 3,913 patients,preliminarily reported a difference in favor of Ki-67 suppressionfor letrozole (in a nonrandomized comparison), the Ki-67 sup-pression difference detected in this large study did not translateinto a clinically relevant difference in FACE.8 The POETIC resultis useful, however, because it indicates that the power producedby smaller neoadjuvant or presurgical trials with , 5% of the sizeof an adjuvant trial produces sufficient Ki-67 data to reject anadjuvant design.

We strongly recommend that there be an absolute require-ment for positive Ki-67 data from the neoadjuvant endocrinesetting before embarking on a decades-long effort to completean adjuvant investigation in estrogen receptor–positive breastcancer. In this regard, the marked antiproliferative effects ofpalbociclib, a CDK4/6 inhibitor, when added to anastrozole inthe NeoPalAna study suggests that adjuvant CDK4/6 studies willlikely produce positive outcomes.9

Rodrigo GoncalvesFaculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

Table 1. Summary of Clinical Trial Conclusions That Compared Endocrine Agents in the Neoadjuvant and Adjuvant Settings for Endocrine Agents in Breast Cancer

Adjuvant Trial Neoadjuvant Trial (Ki-67 Analysis)

Study (No. of Patients) Results* Study (No. With Available Ki-67 Data) Results†

BIG 1-98 (8,050) Letrozole . tamoxifen PO24 (185) Letrozole . tamoxifenATAC (9,366) Anastrozole . tamoxifen and

anastrozole 1 tamoxifenIMPACT (259) Anastrozole . tamoxifen and

anastrozole 1 tamoxifenMA27 (7,576) Anastrozole 5 exemestane ACOSOG Z1031 (266‡) Anastrozole 5 exemestaneFACE (4,136) Letrozole 5 anastrozole ACOSOG Z1031 (266‡) Letrozole 5 anastrozole

Abbreviations: ., superior; ACOSOG, American College of Surgeons Oncology Group; ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG, Breast InternationalGroup; FACE, Letrozole (Femara) Versus Anastrozole Clinical Evaluation; IMPACT, Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen; Ki-67,protein encoded by the MKI67 gene.*On the basis of events.†On the basis of levels of Ki-67 before and after aromatase inhibitor.‡The number of patients with baseline and on-treatment Ki-67 values in the three-way comparison in the Z1031 trial were anastrozole, n5 86; exemestane, n5 91; andletrozole, n 5 89.

Corresponding author: Matthew J. Ellis, MD, PhD, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza,Houston, TX 77030; e-mail: [email protected].

© 2017 by American Society of Clinical Oncology 1

Downloaded from ascopubs.org by Hospital Universitario de Cruces-Servicio de Biblioteca de Ciencias de la Salud on June 8, 2017 from 212.142.248.135Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Dowse[ M JCO 2005 Gonçalves R. JCO 2017

Cambio de Ki 67 a corto plazo (2s) Correlación con resultados en adyuvancia – nivel de ensayo clínico

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Robertson JFR SABCS 2017

Cambio de Ki 67 a corto plazo (2s) A nivel invidual ?? Estudio POETIC (HR+, 60%N0 95% T1-‐2. -‐  2s de HT neoà [o según

prác0ca) -‐  Ki67 basal-‐ Ki2w (cut off 10%) -‐  2 semanas de HT neo – no

impacto en SV vs [o estandar -‐  Ki 67 basal bajo o descenso a bajo

– Factor pronós5co

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NAH – Luminal A (4) PEPI score (preopera:ve endocrine prognos:c index) •  Basado en resultados de la pieza quirúrgica tras HT neo (>3 m)

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relapse risk; 3.7% at 5 years versus 14.4% at 5 years for PEPI greater than 0, based on119 cases36 (Table 7).

Multigene Expression Tests

Prediction analysis of microarray 50Prediction analysis of microarray 50 (PAM50) is 50-gene quantitative polymerasechain reaction assay developed to identify the intrinsic biological breastcancer subtypes (luminal A/B, HER2 enriched, basal like). A risk of recurrencescore is derived from the expression profile of the genes, with special weightinggiven to a set of proliferation-associated genes, with tumor size also included.The commercial Prosigna test (Nano String Technologies, Inc.) is Food and DrugAdministration approved as a prognostic predictor of postmenopausal womenwith lymph node–negative, HR-positive, and HER2-negative breast cancer treatedwith adjuvant endocrine therapy.41

Four-gene panelRecently it has been demonstrated that a 4-marker immunohistochemistry panel (ER,PR, HER2, and Ki67), distinguishes luminal A from luminal B breast cancer subtypesand may be useful in selecting adjuvant therapy and predicting long-term outcomes.42

Although it is an inexpensive test with prognostic utility, the lack of reproducibility ofthe 4-marker immunohistochemistry panel is problematic. Differences can occurbecause of variability in several factors, including fixation, antigen retrieval, reagents,and interpretation.43

Oncotype DX 21-gene recurrence scoreOncotype DX is an reverse transcription–polymerase chain reaction–based multi-gene analysis that predicts recurrence in ER-positive, lymph node–negative breast

Table 7The preoperative endocrine prognostic index score

Pathology, Biomarker Status

Recurrence-free SurvivalBreast Cancer–specific

Survival

Hazard Ratio Points Hazard Ratio Points

Tumor size

T 1/2 — 0 — 0

T 3/4 2.8 3 4.4 3

Node status

Negative — 0 — 0

Positive 3.2 3 3.9 3

Ki67 level

0%–2.7% — 0 — 0

>2.7%–7.3% 1.3 1 1.4 1

>7.3%–19.7% 1.7 1 2.0 2

>19.7%–53.1% 2.2 2 2.7 3

>53.1% 2.9 3 3.8 3

ER status, Allred score

0–2 2.8 3 7.0 3

3–8 — 0 — 0

Grossman et al132

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PEPI risk score 0, 1–3, and ≥4 Modified PEPI-‐ 0 vs Non 0

Ellis MJ. JNCI 2008

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endocrine prognos0c index)

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1386 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008

adjuvant chemotherapy was tabulated by PEPI risk group for both studies ( Figure 3, E [P024] and F [IMPACT]). The per-centages of patients who were treated with chemotherapy in PEPI group 1 (no risk points) were 12% (P024) and 3% (IMPACT ), too low for chemotherapy to have had a major role in producing the favorable outcomes observed in this group. The heat maps in Figure 3 , E and F, serve to display the distri-bution of adverse factors in the two studies. These data illustrate the mixed nature of the intermediate group of tumors (PEPI score 1 – 3), which consisted of either low-stage tumors with adverse biomarkers or higher-stage tumors with favorable bio-markers. Ultimately, the clinical signifi cance of the PEPI model lies in its ability to identify patients at low risk of relapse in the absence of adjuvant chemotherapy (group 1) and patients at very high relapse risk that should mandate all appropriate adjuvant treatments (group 3). More confi dence around the estimates of

relapse risk assigned to PEPI group 2 will require studies with larger sample sizes and longer follow-up. Finally, because of the shorter follow-up, there were too few deaths in the IMPACT trial to validate the PEPI model for the prediction of BCSS.

Discussion Neoadjuvant endocrine therapy has been widely adopted as a prac-tical means to improve surgical outcomes for postmenopausal women with ER+ stage 2 and 3 breast cancer ( 14 ), but little was known about how the post–neoadjuvant endocrine therapy patho-logical stage and biomarker status could be used to make decisions regarding other adjuvant treatments. To address this question, we integrated information on standard pathological staging parame-ters after neoadjuvant endocrine therapy with measurements of ER status and levels of the Ki67 proliferation antigen in the surgical

Figure 3 . Development and validation of the Preoperative Endocrine Prognostic Index (PEPI). A ) Relapse-free survival (RFS) for the three PEPI risk groups identifi ed in the P024 model with a log-rank statistic to test the overall trend ( P < .001). The green line represents group 1, patients with a PEPI risk score of 0; the red line group 2, a PEPI risk score of 1 – 3; and the purple line group 3, a PEPI risk score of 4 or more. The three groups have distinct risks of relapse. B ) PEPI groups 1, 2, and 3 also have distinct risks of breast cancer death, with similar statistical sig-nifi cance as the RFS data ( P < .001). C ) The PEPI model was validated in the IMPACT trial for RFS, with a statistically signifi cant association between relapse risk and risk score ( P = .002). D ) Pathological stage (stage 1 or 0 [ green line ] vs stage 2 or 3 [ red line ]) has a distinctly favor-able outcome in the IMPACT trial ( P = .03). Of 43 patients in the stage 1 or 0 group, only one experienced relapse. This patient’s tumor had the highest Ki67 level in the stage 1 or 0 group, and had therefore been correctly assigned to PEPI group 2. E ) Top, relationships among risk score, relapse events, and adjuvant chemother-apy administration (Chemo) in patients in the P024 trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. F ) Top, relationships among risk score, relapse events, and adjuvant chemother-apy administration (Chemo) in patients in the IMPACT trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. The heat maps indicate the pres-ence of a favorable factor ( green ) or an adverse factor ( red ) for large tumor size, node-positive status, or estrogen receptor (ER) negativity. The color coding in the Ki67 line of the heat map indicates Ki67 with a risk point of 0 as green , a risk point of 1 as dark red , and risk point of 2 as red . The bar over the heat map indicates the three risk groups generated by the risk point assignments ( green , group 1; red, group 2; and purple, group 3).

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•  Ki 67 – insuficiente validez analí0ca –  variabilidad interobservadores alta –  Intento de estandarización –  Extensión de resultados al paciente individual di�cil –  Cambio a QT si no descenso a < 10% – ACOSOG Z1031-‐ pCR 5,7% (inferior a la esperada)

•  PEPI –  Se basa en Ki 67 –  N+ dada la baja % de pCR es raro que se puedan conver0r en un PEPI score 0 – la mayoria de N0 probables cN0 al Dx

23 Dowse[ M JNCI 2011 Leung SCY NPG Breast Cancer 2016 Ellis MJ: JCO 2017

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¿Neoadyuvancia o cirugía de entrada?

•  En la prác0ca habitual Si el tamaño no es criterio de No CS o la paciente prefiere mastectomía– Cirugía y tomar decisión de tratamiento posterior en fución de pTNM, biomarcadores IHQ y moleculares

•  ¿Cuándo NAH? – Facilitar CS-‐ (HT?, QT?) –  Inves0gación: ENSAYOS CLINICOS BIEN DISEÑADOS

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#seom2018* - seom: sociedad espa · t3 n1 m0 iiia t3 n2 m0 iiia t4 n0 m0 iiib t4 n1 m0 iiib t4 n2...

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