Benefit of the 70-gene profile for widely used guidelines: an answer to increased selection for adjuvant chemotherapy in breast cancer

Benefit of the 70-gene profile for widely used guidelines:

an answer to increased selection for adjuvant chemotherapy in breast cancer

The New Dutch Guidelines

Abstract

Background

Discussion

Risk assessment for breast cancer patients differs substantially among the different treatment guidelines. The National Comprehensive Cancer Network (NCCN), St.Gallen, Adjuvant!Online, and Dutch 2008 guidelines are less restrictive in comparison to the 2004 Dutch guidelines and the Nottingham Prognostic Index (NPI), when selecting patients for adjuvant systemic treatment.

Introduction:

Risk assessment for breast cancer patients differs substantiallyamong treatment guidelines. The NCCN, St.Gallen, Adjuvant!Online, and Dutch 2008 guidelines are less restrictive in comparison to the 2004 Dutch guidelines and Nottingham Prognostic Index, when selecting patients for adjuvant systemic treatment. The Dutch Institute for Healthcare Improvement (CBO) has introduced slight changes in the concept 2008 guidelines. Adjuvant systemic treatment is only advised when the absolute 10-years survival benefit is 5% or more. The new recommendations for adjuvant systemic treatment are based on survival tables used in the Adjuvant! software. The changes affect only node-negative patients aged >35 years: since 2008 patients with G2/G3 tumors >1cm or every tumor >2cm are advised to undergo adjuvant systemic therapy, while in 2004 this was the case for tumors G3>1cm, G2>2cm or every tumor >3cm.

Patients and Methods:

Risk was assessed for 427 lymph-node negative (LNN) patients in the prospective RASTER-study (Bueno-de-Mesquita, 2007) and 151 LNN patients in the NEJM-series (van de Vijver, 2002). Clinical risk was calculated using the 2004 and 2008 Dutch guidelines. Genetic risk was assigned according to the result of the Amsterdam 70-gene signature. Survival analyses were done according to the univariateKaplan-Meier-method.

Results:

Instead of 57% in 2004, in 2008 only 24% of patients were assigned to clinical low risk in the RASTER study, and 141 patients (33%) changed from low to high risk (p<0.001). The rate of discordant findings between clinical assessment and 70-gene signature increased from 30% in 2004 to 41% in 2008 (p<0.001, table 1). Similar results were obtained for the 151 patients of the NEJM-series (30% and 35% discordance for the 2004 and 2008 CBO guidelines, respectively). At 10 years follow-up, differences between the high and low risk categories according to the 2004, 2008 guidelines and the 70-gene profile, were best predicted by the latter: distant-disease-free survival (DDFS) log-rank p=0.002, p=0.11 and p<0.001 respectively.

Discussion:

As adjuvant systemic treatments become more effective, guidelines become less restrictive, resulting in more patients being selected for adjuvant therapy. Since newer treatment guidelines do not better predict survival, the magnitude of the 70-gene profiles benefit, which is defined as proportion of patients in whom over-and undertreatmentcan be avoided, depends on present guidelines for risk assessment and shows a remarkable increase.

31st Annual

San Antonio

Breast

Cancer

Symposium, December 10 – 14, 2008, San Antonio, Texas, USA

As adjuvant systemic treatments become more effective, guidelines become less restrictive, resulting in more patients being selected for adjuvant therapy. Since newer treatment guidelines do not better predict survival, the magnitude of the 70-gene profiles benefit, which is defined

as proportion of patients in whom over-and undertreatment

can be avoided, depends on present guidelines for risk assessment and shows a remarkable increase for the newer guidelines.

Abstract # 1084

Introduction

Patients and Methods

The Dutch Institute for Healthcare Improvement (CBO) has introduced slight changes in the concept 2008 guidelines. The recommendations for adjuvant treatment are based upon survival tables used in the Adjuvant! software (1) and

overlap substantially with the new St. Gallencriteria (2).

Adjuvant systemic treatment is only advised when the absolute 10-year survival benefit is 5% or more. The changes affect only node-negative patients aged >35 years: since 2008 patients with G2/G3 tumors >1cm or every tumor >2cm are advised to undergo adjuvant systemic therapy, while in 2004 this was the case for tumors G3 >1cm, G2 ≥2cm or every tumor >3cm. Notably, in contrast to other guidelines regarding the hormone receptor status, in the 2004 Dutch guidelines, adjuvant endocrine treatment was advised only in clinically high-risk patients with

hormone-receptor-positive tumorsin combination with chemotherapy.

This has changed in the 2008 guidelines as follows: the Adjuvant! software may help in determining outcome for patients treated with chemotherapy and/or hormone therapy.

Survival: Guidelines and 70-gene profile

Risk was assessed for 427 lymph node negative patients in the prospective RASTER-study (3) (Bueno-de-Mesquita et al, 2007), that was performed between 2004 and 2006 in 16 community-based hospitals in the Netherlands as well as for the 151 lymph node negative patients in the NEJM-series (4)

(van de Vijveret al, 2002). Clinical risk was calculated using

the 2004 and 2008 Dutch guidelines as well as the present St.Gallen guidelines and the Nottingham Prognostic Index. Genetic risk was assigned according to the result of the Amsterdam 70-gene signature (MammaPrint™).

Survival analyses were done according to the

Kaplan-Meier-method.Discordancewas measuredbyCohen’skappa

coefficientand significancefordiscordanceinterpretedby

the Landis-Kochmethod(5).

Discordance: Guidelines and 70-gene profile

population, and 141 patients (33%) changed from low to high risk (p<0.001) with a κ=0.385, suggesting only fair agreement between the guidelines. The rate of discordant findings between clinical assessment and 70-gene signature increased from 30% in 2004 to 41% in 2008 (p<0.001). Details for NPI and St.Gallen guidelines are shown in table 1. Similar results were obtained for the 151 patients of the NEJM-series: The proportion of patients assigned to clinical low risk was halved from 43% to 19% in the 2008 guidelines. With κ=0.48, suggesting moderate agreement, 36 patients

changed from low risk to high risk in 2008.The discordance

between the 70-gene signature and the 2004 and 2008 CBO guidelines changed from 30% to 35% in 2008 respectively,

with κfalling from 0.386 to 0.196, suggesting now only slight

agreement. At 10 years FU, differences between the high and low risk categories according to the 2004, 2008, St.Gallen guidelines and the 70-gene profile, were best predicted by the latter: distant disease-free survival (DDFS) log-rank p=0.002, p=0.11, p=0.12 and p<0.001 respectively.

References:

(1) RavdinPM et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J ClinOncol2001 Feb 15;19(4):980-91

(2) GoldhirschA et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol2007 Jul;18(7):1133-44

(3) Bueno-de-Mesquita JM et al. Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol2007 Dec;8(12):1079-87 (4) van de Vijver MJ et al. A gene-expression signature as a predictor of survival in breast cancer. N EnglJ Med 2002 Dec 19;347(25):1999-2009

(5) LandisJR et al. The measurementof observeragreementforcategoricaldata. Biometrics1977 Mar;33(1):159-74

Michael Knauer MD DSc

_{, V Retèl}

_MSc

_{, JM Bueno-de-Mesquita MD}

_{, EJT Rutgers MD,PhD}

_{, WH van Harten}

_MD,PhD

_{, S Rodenhuis}

_MD,PhD

_{, MJ van de Vijver}

_MD,PhD

LJ van 't Veer PhD

_{and SC Linn MD,PhD}

1: Netherlands Cancer Institute, 2: Academic Medical Center and 3: Agendia

BV, Amsterdam, Netherlands

RASTER-study (n=427) 70-gene signature low risk 70-gene signature high risk Discordant findings n (%), kappa Dutch 2004 Low 243 (56.9) 168 (39.3) 76 (17.8) 127 (29.7) κ= 0.403 High 184 (43.1) 51(11.9) 132 (30.9) Dutch 2008 Low 103 (24.1) 74 (17.3) 29 (6.8) 174 (40.8) κ= 0.196 High 324 (75.9) 145 (34.0) 179 (41.9) St.Gallen Low 75 (17.6) 63 (14.8) 12(2.8) 168 (39.3) κ= 0.226 High 352 (82.4) 156 (36.5) 196 (45.9) NPI Low 248(58.1) 175 (41.0) 73 (17.1) 117 (27.4) κ= 0.450 High 179 (41.9) 44 (10.3) 135 (31.6)

Results

Rates of discordant findings between the different guidelines and the Amsterdam 70-gene signature MammaPrint™. Risk was assessed for 427 lymph node negative patients from the RASTER-study.

Abbreviations: n, number of patients; NPI, Nottingham PrognosticIndex; κ, discordance by Cohen’s kappa coefficient

CBO 2004 Guidelines 0 2 4 6 8 10 0 20 40 60 80 100

CBO 2004 low risk CBO 2004 high risk Log-rank (Mantel-Cox) Test

P value 0.0021 Time in years S ur vi va l pr obab ili ty CBO 2008 Guidelines 0 2 4 6 8 10 0 20 40 60 80 100

CBO 2008 low risk CBO 2008 high risk

Log-rank (Mantel-Cox) Test P value 0.1113 Time in years S ur vi va l pr obab ili ty St.Gallen Guidelines 0 2 4 6 8 10 0 20 40 60 80 100

St.Gallen low risk St.Gallen high risk

Log-rank (Mantel-Cox) Test P value 0.1188 Time in years S ur vi va l pr obab ili ty MammaPrint 0 2 4 6 8 10 0 20 40 60 80 100

MammaPrint low risk MammaPrint high risk Log-rank (Mantel-Cox) Test

P value < 0.0001 Time in years S ur vi va l pr obab ili ty