The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer

Abstract

IntroductionSUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance.Patients and methodsA single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment.ResultsThe major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N−) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N− cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N− cases, 4.1% of all cases).ConclusionsThese data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4145-4) contains supplementary material, which is available to authorized users.

Post-mastectomy Radiotherapy in T1-2 Breast Cancer Patients With One to Three Lymph Node Metastases: A Propensity Score Matching Analysis

“…The limitations of our study were that the SEER database did not provide details of the irradiated technique and scope, the absence of local regional recurrence data, and that the molecular subtype information only gotten from the year 2010 resulted in a small sample size and short follow-up time for subgroup analysis. We look forward to the results of the prospective SUPREMO trial, which randomly allocated breast cancer patients with highrisk node-negative disease and those with one to three positive nodes to receive PMRT or not (32). The results of this trial may eventually help determine which patients are most likely to benefit from PMRT when modern systemic treatment and surgery are used.…”

Trends and variations in postmastectomy radiation therapy for breast cancer in patients with 1 to 3 positive lymph nodes: A National Cancer Data Base analysis

“…In the Selective Use of Post Mastectomy Radiotherapy (SUPREMO) trial, which closed to accrual in 2013, the role of PMRT without the inclusion of regional lymph node areas was investigated in 1300 patients who had intermediate-risk breast cancer, defined as T1N1, T2N1, or T2N0 with grade 3 or lymphovascular invasion. 24 Forthcoming data from these trials using contemporary systemic therapy and RT regimens will provide rich opportunities to derive prognostic and predictive assays for local recurrence risk and radiosensitivity, respectively, in women who have breast cancer with 1 to 3 positive lymph node. 25 However, information obtained from these assays must be balanced against the cost effectiveness of routinely using such strategies to guide decision making in these patients.…”

Post-mastectomy radiation in node-positive breast cancer in Ontario

“…These new therapies may reduce the rates of loco‐regional recurrence sufficiently in patients with 1‐3 positive nodes that the use of radiotherapy is unnecessary . The effectiveness of post‐mastectomy radiation with modern systemic therapy in T1/2 tumors with 1‐3 positive nodes will be determined by the SUPREMO trial; however, study results will not be available for several years.…”