Comparison of Radiation With or Without Concurrent Trastuzumab for HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy: A Phase III Clinical Trial

Abstract

PURPOSE Preclinical studies report that trastuzumab (T) can boost radiotherapy (RT) effectiveness. The primary aim of the B-43 trial was to assess the efficacy of RT alone vs concurrent RT plus T in preventing recurrence of ipsilateral breast cancer (IBTR) in women with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS Eligibility: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, DCIS resected by lumpectomy, known estrogen receptor (ER) and/or progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status by centralized testing. Whole-breast RT was given concurrently with T. Stratification was by menopausal status, adjuvant endocrine therapy plan, and nuclear grade. Definitive intent-to-treat primary analysis was to be conducted when either 163 IBTR events occurred or all accrued patients were on study ≥ 5 years. RESULTS There were 2,014 participants who were randomly assigned. Median follow-up time as of December 31, 2019, was 79.2 months. At primary definitive analysis, 114 IBTR events occurred: RT arm, 63 and RT plus T arm, 51 (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.17; P value = .26). There were 34 who were invasive: RT arm, 18 and RT plus T arm, 20 (HR, 1.11; 95% CI, 0.59 to 2.10; P value = .71). Seventy-six were DCIS: RT arm, 45 and RT plus T arm, 31 (HR, 0.68; 95% CI, 0.43 to 1.08; P value = .11). Annual IBTR event rates were: RT arm, 0.99%/y and RT plus T arm, 0.79%/y. The study did not reach the 163 protocol-specified events, so the definitive analysis was triggered by all patients having been on study for ≥ 5 years. CONCLUSION Addition of T to RT did not achieve the objective of 36% reduction in IBTR rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of RT plus T is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy.

Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

“…To date, studies have either found unclear or weak evidence of HER2 status as a prognostic indicator in DCIS, [4][5][6][7] and no statistically significant benefit to the use of trastuzumab concurrently with radiation in HER2 amplified DCIS. 8 The NCCN Panel has concluded that HER2 status for DCIS does not alter the management strategy and therefore is not recommended for DCIS.…”

A Novel Biosignature Identifies Patients With DCIS With High Risk of Local Recurrence After Breast Conserving Surgery and Radiation Therapy

“…The study was powered to detect a 36% reduction in ipsilateral breast tumor recurrence; however, owing to a limited number of events, the trial demonstrated only a nonsignificant but potentially clinically relevant reduction of 19%. 21 Given this 19% reduction in ipsilateral breast tumor recurrence, the results of B-43 suggested that HER2 may be associated with identifying this cohort of patients with high-risk DCIS. Based on the present study results, one may expect that some but not all patients with HER2-mediated DCIS may be at higher-than-expected risks of recurrence after BCS plus RT, because they were overrepresented in the Residual Risk group.…”

Molecular subtypes predict second breast events of ductal carcinoma in situ after breast‐conserving surgery

“…Cesare et al 30 confirmed that HER2 positive status in DCIS was associated with high nuclear grade ( p < 0.001) and high Ki‐67 expression ( p = 0.003). Based on these findings, the NSABP B‐43 study 31 explored whether the use of trastuzumab in HER2‐positive DCIS patients could reduce ipsilateral recurrence. After 79.2 months of follow‐up, the radiotherapy plus trastuzumab arm achieved a modest, but statistically nonsignificant decrease of 19% in ipsilateral recurrence rate.…”