Abstract No. 
San Antonio Breast Cancer Symposium
Deceber 10-14

MammaPrint ultra-high risk score is associated with response to neoadjuvant chemotherapy in the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

Wolf DM, Daemen A, Yau C, Davis S, Boudreau A, Swigart L, Investigators I-SPY1Trial, Esserman L, van'tVeer L

Background: Increasingly, gene expression tests are being used with standard clinicopathological markers to assess risk of recurrence in breast cancer and to guide treatment. The 70-gene signature (MammaPrint™) was recently validated in a prospective study as an effective tool for identifying low risk patients who may avoid chemotherapy without compromising outcome. MammaPrint scores have been shown to differentiate likelihood of neoadjuvant chemotherapy response. Here we hypothesize that a further stratification of the 70-gene signature into ‘high-risk’ and ‘ultra-high risk’ groups might yield improved predictors of chemo-sensitivity and patient outcome. 

Methods: Agilent 44K array data from pre-treatment biopsies were obtained from 149 I-SPY 1 TRIAL patients treated with neoadjuvant anthracycline-based chemotherapy. These data were used to compute each patient's MammaPrint score and risk category (good vs. poor threshold 0.4). Of these patients, 138 were either in the ‘poor’ outcome group (136) or in the ‘good’ outcome group but Her2+ (2). The median score cut-point based on these 138 patients equals -0.154, and was used to further stratify patients into MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2) groups, with MP1 defined as ≤ -0.154 and MP2 defined as >-0.154 (69 MP1, 69 MP2). Outcome parameters included pathologic complete response (pCR) after therapy and recurrence free survival (RFS). Fisher's exact test was used to assess association with pCR overall and within hormone receptor (HR) and Her2 subtypes, and Cox proportional hazards modeling to assess association with RFS. 29 patients who received Herceptin and 4 without pCR data were excluded from analysis, yielding 105 evaluable patients. 

Results: Though all receptor subtypes were represented in MP1 and MP2 subgroups, the majority of MP1 patients were HR+/Her2- (54%), whereas MP2 patients were more evenly distributed among triple negative (TN; 38%), HR+/Her2- (22%), HR-/Her2+ (22%) and HR+/Her2+ (18%) subtypes. 25/105 patients achieved pCR: 8 (15%) in the MP1 group and 17 (33%) in the MP2 group. Applying Fisher's exact test, we found that a significantly higher percentage of pCR was observed for MP2 patients in the overall population (p = 0.038), but not within receptor subtypes; though there was a trend towards a higher pCR rate in MP2 patients within the HR+/Her2- subset (p = 0.071). The greater sensitivity of MP2 to chemotherapy may in part be driven by differences in receptor subtype distribution, as well as a relationship between MP2 status and proliferation; we found that MP1/2 classification was highly associated with Ki67 (low/intermediate: <25% positive; high:>25% positive) (p = 3.3E-5), with MP2 patients having more Ki67 positive cells. No significant differences in RFS were observed between MP1 and MP2 subsets, likely because MP2 patients, who respond best, are also at the highest risk of relapse. 

Conclusion: These analyses suggest that additional MammaPrint score stratification within the ‘poor’ biology group might be a useful for developing companion diagnostics to neoadjuvant therapies, a hypothesis currently being tested in the adaptive randomization engine of the I-SPY 2 clinical trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-01.

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