Background

Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients as tumors with seemingly similar biology can have strikingly different clinical outcomes. We analyzed response to neo-adjuvant chemotherapy as a function of molecular sub-types and show patient survival from the multi-center neo adjuvant trial, I-SPY I (CALGB 150007/150012; ACRIN 6657). Previous analyses had shown that breast cancer subtypes as identified by immunohistochemistry or molecular analyses, have distinct clinical outcome (Esserman, ASCO 2009). Here, we analyze how the 70-gene signature (MammaPrint) together with an 80-gene molecular subtyping profile (BluePrint=Basal-type, Luminal-type, ERBB2-type; de Snoo, ASCO, 2010 and manuscript under review) can sub-classify patients.

Materials: This study was carried out on genomics data of core needle biopsies from 149 out of 221 patients enrolled in the I-SPY I trial, a multi-center trial designed to identify predictive markers of pathological complete response (pCR) and disease-free survival (DFS) in women with locally advanced breast cancer (3 cm or greater). All women received neoadjuvant Doxorubicin & Cytoxan followed by paclitaxel chemotherapy. The 70-gene and the subtyping signatures, Basal, Luminal and ERBB2-type were determined on 44K Agilent arrays available through the I-SPY 1 data portal (Esserman, ASCO, 2009 and manuscript under review).

Results: The 70-gene signature classified 9% of patients (13/149) as Low Risk, of whom one patient was ERBB2-type, and the other 12 were Luminal-type. None of these patients experienced a pCR. The remaining 136 were classified as 70-gene High Risk (91%), of whom 47% were classified as Luminal-type with a pCR rate of 13%, 41% were Basal-type with a pCR rate of 34%, and 12% were ERBB2-type with a pCR rate of 56%.

Patients with BluePrint Basal-type tumors had a 5-year DFS of 61%; ERBB2-type had a 5-year DFS of 78%; 70-gene High Risk/Luminal-type had a 5-year DFS of 73% and 70-gene Low Risk/Luminal-type showed 5-year DFS of 100%.

The molecular subtype classification shows significant association to clinically assessed receptor status. However, clinically assessed HER2+ patients were distributed across all molecular subtypes, where ER+HER+ are predominantly classified as Luminal-type.

Conclusion: This study was performed with the I-SPY I dataset, which provides a platform to compare, contrast & combine marker signatures to tailor therapy. We show how combining BluePrint, with MammaPrint risk-classification can detect specific groups of patients who are at high risk of recurrence and who would have a higher likelihood to benefit from chemotherapy. Furthermore, MammaPrint Low Risk patients do not benefit from neo-adjuvant therapy, though have excellent survival rates, suggesting that the Low Risk Luminal-type patients could be managed conservatively.