Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1)

Abstract

Background: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions.

Patients and methods: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed.

Results: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94).

Conclusion: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Keywords: Prosigna; adjuvant treatment; chemotherapy; decision impact; early breast cancer; endocrine treatment.

Figure 1

Schematicoverview of the study. ^aIneligible: Previous or concurrent cancer diagnosis (n = 11), distant metastases (n = 1), HER2+ (n = 2), pT2 N1(mi) (n = 6), DCIS only (n = 1), pN1 (n = 3), pNx due to other diseases (n = 3), patient not able to comply with protocol (n = 1) and screening failure, reason not specified (n = 7). ^bProsigna test not applicable: Patient consent withdrawn before test (n = 6), insufficient tumour material for RNA extraction or low tumour cell count (n = 28), other reasons not specified (n = 1). Study start: 01 October 2018. DCIS, ductal carcinoma in situ; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MDT, multidisciplinary team.

Figure 2

Treatment decision alterations. Treatment decision alteration for (A) pN0 total study population with conclusive Prosigna test result, (B) patients aged ≤50 years and (C) patients >50 years of age. Pre-test: Treatment decision before knowledge of the Prosigna test result. Post-test: Treatment decision after the Prosigna test result was declared. CT, chemotherapy; ET, endocrine therapy; NT, no systemic treatment. ^a% of Pre-Prosigna decision.

Figure 3

Treatment decision across hospitals (site 1-14, with more than 50 patients included) for patients with pT1c-pT2 pN0. No-chemo candidates: G2 and Ki67< 0.5× local laboratory median score or G1 and Ki67 <1× local laboratory median score. Uncertain chemo candidates: G2 and Ki67 0.5-1.5× local laboratory median score. Chemo candidates: G2 and Ki67 >1.5× local laboratory median score or G3 and Ki67 >1× local laboratory median score. Treatment decision without Prosigna test (A-C). Treatment decision with Prosigna test (D-F). CT, Chemotherapy; ET, endocrine therapy; NT, no systemic treatment.

Figure 4

Ki67-Risk Of Recurrence (ROR) scatterplot of pT1c-pT2 tumours with Ki67 analysed as continuous variable and presented as absolute score value (‘Absolute Ki67’) or normalized to the local laboratory median Ki67 score (‘Normalized Ki67’). (A) G2 and Ki67 <10% or G1 and Ki67 <20%, (B) G2 and Ki67 10%-35%, (C) G2 and Ki67 >35% or G3 and Ki67 >20%, (D) G2 and Ki67 <0.5× local laboratory median score or G1 and Ki67 <1× local laboratory median score, (E) G2 and normalized Ki67 0.5-1.5× local laboratory median score, and (F) G2 and normalized Ki67 >1.5× local laboratory median score or G3 and normalized Ki67 >1× local laboratory median score. In (A-B and D-E), the parts of the figures containing data points are enlarged in the upper right corner.