21-Gene Assay and Breast Cancer Mortality in Ductal Carcinoma in Situ

Eileen Rakovitch, MD, MSc, FRCPC; Rinku Sutradhar, PhD; Sharon Nofech-Mozes, MD, FRCPC; Sumei Gu, MSc; Cindy Fong, BSc, CCRP; Wedad Hanna, MD, FRCPC; Lawrence Paszat, MD, MSc, FRCPC

Disclosures

J Natl Cancer Inst. 2021;113(5):572-579. 

In This Article

Abstract and Introduction

Abstract

Background: The inability to identify individuals with ductal carcinoma in situ (DCIS) who are at risk of breast cancer (BC) mortality have hampered efforts to reduce the overtreatment of DCIS. The 21-gene recurrence score (RS) predicts distant metastases for individuals with invasive BC, but its prognostic utility in DCIS is unknown.

Methods: We performed a population-based analysis of 1362 individuals of DCIS aged 75 years or younger at diagnosis treated with breast-conserving therapy. We examined the association between a high RS (defined a priori as >25) and the risk of BC mortality by using a propensity score-adjusted model accounting for the competing risk of death from other causes, testing for interactions. All statistical tests were 2-sided.

Results: With 16 years median follow-up, 36 (2.6%) died of BC, and 200 (14.7%) died of other causes. The median value of the RS was 15 (range = 0–84); 29.6% of individuals had a high RS. A high RS was associated with an 11-fold increased risk of BC mortality (hazard ratio = 11.27, 95% confidence interval [CI] = 3.00 to 42.33; P < .001) in women aged 50 years or younger at diagnosis treated with breast-conserving surgery alone, culminating in a 9.4% (95% CI = 2.3% to 22.5%) 20-year risk of BC death. For women with a high RS, treatment with radiotherapy was associated with a 71% (hazard ratio = 0.29, 95% CI = 0.10 to 0.89; P = .03) relative and a 5% absolute reduction in the 20-year cumulative risk of death from BC.

Conclusion: The 21-gene RS predicts BC mortality in DCIS and combined with age (50 years or younger) at diagnosis can identify individuals for whom radiotherapy reduces the risk of death from BC.

Introduction

Ductal carcinoma in situ (DCIS) is a malignant, clonal proliferation of epithelial cells without stromal invasion.[1] Individuals with DCIS have a low risk of breast cancer mortality (2%-3% at 10 years).[2] Despite this, guidelines recommend treatment because of the potential of DCIS to recur as invasive cancer, which is associated with a higher risk of breast cancer mortality.[3,4] Most women with DCIS are treated with breast-conserving surgery (BCS) followed by breast radiotherapy (RT), which has been proven in randomized trials to reduce the risk of local recurrence (LR).[2] Although breast RT is well tolerated, it is associated with skin irritation and rare but serious adverse effects such as cardiac events and RT-induced malignancies.[5,6] Given the indolent behavior of most DCIS lesions, and the lack of proven survival benefit with RT, there is interest to de-escalate its treatment.[7,8]

Currently, clinicians use features such as age at diagnosis, grade, presence of necrosis, tumor size, and resection margin status[4,9,10] to estimate the risk of LR after BCS and guide treatment decision making; however, these factors are not associated with an increased risk of breast cancer mortality. The inability to distinguish patients with biologically aggressive DCIS (who require treatment) from those with indolent disease explains why most women continue to receive RT[11] and why efforts to de-escalate treatment of DCIS have been elusive.

The Oncotype DCIS Score (DS) (Exact Sciences, CA Prelude DX, CA) and the DCISionRT assay (PreludeDx) are molecular expression assays that predict the risk of LR after BCS.[12–16] The DS comprised 12 of the 21 genes of the Oncotype DX breast recurrence score (RS) (Exact Sciences), which is prognostic for patients with early invasive breast cancer[17,18]—a high RS predicts a higher risk of metastases and worse survival[19,20]—but the ability of the 21-gene RS to predict breast cancer mortality in DCIS is unknown.

We examined the association of the 21-gene RS with breast cancer mortality in DCIS. Specifically, we examined the frequency of high RS expression [defined a priori as >25[20]] in index DCIS lesions and its impact on the risk of breast cancer mortality after BCS for DCIS.

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