Abstract PD7-01: Can surrogate pathological subtyping replace molecular subtyping? Outcome results from the MINDACT trial
Authors: Cardoso F , Slaets L , de Snoo F , Bogaerts J , van 't Veer LJ , Rutgers EJ , Piccart-Gebhart MJ , Stork-Sloots L , Russo L , Dell'Orto P , Viale G 
Published: March 2017

Abstract
Background
Molecular subgroups within early breast cancer (EBC), such as Luminal A, Luminal B, HER-2+, Basal-like may help to best to identify patients for specific treatment regimens. Controversy exists as to which methodology is best at identifying these molecular subgroups. Immunohistochemistry (IHC) may be used as a surrogate method to stratify patients. Molecular subtyping gene expression based tests, such as BluePrint, measure a greater number of genes than pathological criteria. ER, PgR, HER-2 and Ki67 are measured individually at the protein level, while BluePrint is designed to capture the functional underlying biologic pathway regulated by these receptors.
Methods
The MINDACT trial is an international, prospective, randomized, phase III trial which has proventhe clinical utility of MammaPrint in selecting EBC patients who can safely avoid chemotherapy. Here we present the results of a preplanned MINDACT sub-study to compare outcome based on molecular subtyping (MS) to surrogate pathological subtyping (PS) as endorsed by 2013 St. Gallen Consensus. MS data were obtained by MammaPrint (MP) and BluePrint classifying patients in the following subtypes: Luminal A (MP Low Risk); Luminal B (MP High Risk); HER2-type; and Basal-type. ER, PgR, HER2 and Ki67 protein status were centrally assessed by IHC/FISH. The primary hypothesis was that among PS Luminal patients, patients with HER-2+ or Basal-type tumors by MS would have a decreased DMFS compared to MS Luminal patients. At α=5% with 220 events, the study has 80% power to demonstrate this for HR=2.44.
Results
The table depicts classification of tumors according to PS versus MS for all patients (n=5,806).
PS versus MSMSPSLum ALum BHER-2+BasalTotalLum A24562708132747Lum B106979422861971HER-2 enriched1189531826557TN14107500531Total365711693556255806
Most pronounced differences: MS classified 54% as Luminal A among the Luminal B by PS. MS classified 38% as Luminal (A and B) and 5% as Basal-type among the HER-2+ by PS. MS classified 5% as Luminal (A and B) among the TN cases by PS.
MS identifies 63% of patients as Luminal A, while PS identifies 47%; 5yr DMFS for both methods was ≥ 96.0%.
PS Luminal cancers that were classified as HER-2+ or Basal-type by MS had a lower 5yr DMFS (88.0% for HER-2+ and 90.2% for Basal), albeit non-significant, than those who were also Luminal by MS (95.9%): HR= 1.40, 95% CI = 0.75-2.60.
In PS TN cancers, MS identified 24 out of 500 patients (5%) as Luminal-type with excellent prognosis (5yr DMFS of 100% versus 71.4% for MS HER-2+ or 90.1% for MS Basal-type).
Among the PS Luminal patients, Ki67 cut at 20% identified patients with ki67 low (69%), with 5yr DMFS ≥ 96.0% (better compared to the 14% cut-off).
Conclusions
1) MS was able to re-stratify 16% of patients to a low risk Luminal A-type group with an excellent outcome. 2) Among TN EBC, 5% were classified as Luminal by MS and had an excellent outcome. 3) Albeit limited by low numbers of patients in each subgroup, this study suggest that MS is better correlated with outcome. 4) The observed subtype discrepancies may have an impact on treatment decision making. 5) Centrally assessed Ki67 labeling index of 20% may be the best cut-off for surrogate differentiation between Luminal A and B.
Citation Format: Cardoso F, Slaets L, de Snoo F, Bogaerts J, van 't Veer LJ, Rutgers EJ, Piccart-Gebhart MJ, Stork-Sloots L, Russo L, Dell'Orto P, Viale G. Can surrogate pathological subtyping replace molecular subtyping? Outcome results from the MINDACT trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD7-01.