Pat Whitworth, MD of the Nashville Breast Center discusses the 5-year outcomes in the NBRST trial: preoperative MammaPrint and BluePrint breast cancer subtype is associated with neoadjuvant treatment response and survival.
HINTERGROUNDS
MammaPrint (MP) distinguishes patients with breast cancer (BC) who can safely forego adjuvant chemotherapy. BC subtypes with distinct therapeutic response rates and survival results are characterized by MP combined with the BluePrint (BP) molecular subtyping signature. Compared to clinical IHC/FISH approaches, MP and BP reclassified 22 percent of tumors into a separate molecular subtype in the Neoadjuvant Breast Symphony Trial (NBRST). In addition, rates of pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) and partial response to neoadjuvant endocrine therapy (NET) were correctly predicted by MP and BP2. Here, according to MP and BP molecular classification, we record 5-year overall survival (OS) and distant metastasis-free survival (DMFS) in patients from the NBRST registry.
FOR METHODS
From 2011 to 2014, 1072 patients who obtained MP and BP testing were prospectively enrolled in the NBRST trial (NCT01479101). According to NCCN guidelines, patients were assigned to receive NCT or NET and agreed to follow-up for 5 years after surgery (FU). Tumors identified as High Risk (HR) or Low Risk (LR) by MP were further stratified by BP into four subtypes of molecules: Luminal-A, Luminal-B, HER2, and Basal3,4. For 918 patients from 67 US hospitals, clinical results were available. For OS and DMFS, the median FU was 5.2 and 5.0 years, respectively. The Kaplan Meier analysis and the logrank test analyzed the discrepancies in OS and DMFS at 5 years. Using MINDACT criteria for clinical recommendations, clinicopathological risk assessment was performed to identify NET patients as either clinically low risk or clinically high risk 1.
OUTCOMES
22% of tumors have been reclassified as a separate tumor,
Compared to the clinical subtype, the molecular subgroup. ER+ tumors reclassified as Basal by BluePrint (ER+/ BP Basal) were identified by 93 (13%) IHC. HER2+ tumors reclassified as nonHER2 by BluePrint were characterized by 132 (44 percent) IHC/FISH.
Molecular subtyping correctly with MP and BP
Predicted response in patients with BluePrint HER2 and Basal tumors to neoadjuvant care with higher pCR rates.
In the neo-adjuvant environment, MammaPrint remained prognostic. 16% of tumors were identified by MP as Low Risk and 84% as High Risk. In patients with HR, the 5-year DMFS and OS odds were substantially lower relative to LR tumors.
BluePrint projected 5-year clinical results accurately. In patients with Basal and Luminal B tumors, the 5-year DMFS and OS odds were lowest relative to those with Luminal A and HER2 tumors. In the first three years, most DMFS incidents occurred in patients with BP Basal tumors.
Enhanced 5-year DMFS are predicted by pCR in patients with BP Basal tumors.
ER+ tumors that were reclassified as BP Basal and had residual disease after NCT had low 5-year survival in patients. BluePrint further stratified high-risk tumors that were ER+ by IHC into the Luminal B or Basal subtype. Compared to the BP Luminal B group, there was a greater gap in OS between patients who achieved pCR and patients who had the residual disease in the BP Basal group (23.7 percent) (11.1 percent ).
Patients with clinical HER2+ tumors who were treated with trastuzumab (T) with or without pertuzumab (P) and reclassified as BP Basal (HER2+/BP Basal) had substantially lower 5-year OS than patients with HER2+ tumors classified by BluePrint as HER2 or Luminal.
Patients with clinical HER2+ tumors who obtained trastuzumab and pertuzumab (T+P) had worse OS compared to patients with BP Luminal and BP HER2 tumors in those with BP Basal tumors.
CONCLUSIONS INCLUDE
In BC patients undergoing neoadjuvant therapy, MammaPrint remained predictive.
Before surgery, patients with BP Luminal A tumors had a very low risk of progressive disease when using NET alone.
A majority of Luminal A tumor patients who obtained the only NET were clinically high-risk and nevertheless had excellent 5-year DMFS, consistent with MINDACT results.
MP and BP correctly categorized tumors into molecular subtypes and defined the most NCT-responsive subtypes.
For each MP and BP molecular subtype, five-year OS and DMFS were distinct; patients with BP Basal tumors had the worst results, followed by patients with Luminal B, HER2, and Luminal A tumors.
Patients with BP Basal tumors had the highest frequency of events in the first 3 years, demonstrating the crucial need to classify those patients who could benefit from immediate post-surgery secondary therapy.
Clinical ER+ and/or HER2+ tumors that were molecularly basal and displayed distinct treatment responses and substantially worse outcomes were identified by BluePrint relative to tumors with consistent clinical/genomic classification. These ones, these
Optimized CT options, such as those developed for triple-negative breast tumors, may be necessary for patients.
A similar finding in the recent APHINITY research was that clinical HER2+ tumors reclassified as BP Basal did not seem to benefit from dual HER2-targeted therapy (PD3-01).