Abstracts: Thirty-Second Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 10‐13, 2009; San Antonio, TX I-SPY is a multi-center clinical trial designed to identify predictive markers for pathological complete response (pCR), residual cancer burden (RCB) and relapse-free survival (RFS) (median 3.1 yrs) of women with locally advanced breast cancers.237 women were treated in 9 centers with neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel. Gene expression in pre-treatment biopsies from 144 women was analyzed on 44K Agilent arrays, and used to classify the patients by intrinsic subtype-ROR-S, 70-gene prognosis, wound healing and p53-mutation signatures. Individual molecular risk classifications were associated with various rates of response and recurrence. However, discordance for risk classification by at least one of the four prognostic profiles was seen in 57% of patients. Here, we evaluate the meaning of pCR/RCB in relation to 3 year RFS outcome within the context of comprehensive biological make-up of the tumor. Methods: We created a composite Biologically Integrated Prognosis Signature (BIPS) score to represent 'risk categories' as determined by the four classifiers. Assigning scores of either -1 or +1 for two class (low/high) signatures and -1, 0, or +1 for three class (low/intermediate/high) signatures, that were subsequently summed, yielded 31 patients with a good (≥+2), 64 with an intermediate (-3 to +1) and 49 with a poor (-4) BIPS score. Results: pCR/RCB and 3 yr RFS show an inverse correlation for good, intermediate and poor BIPS score patients. Among the 31 patients with a good BIPS score there was poor chemotherapy response (pCR 7%, RCB 0/I 22%), but, regardless of pCR or RCB an invariable 100% 3-year RFS. Intermediate-BIPS- and poor-BIPS-score patients showed increasing chemotherapy response and had a 3-year RFS probability of 80% and 65%, respectively. BIPS score and pCR or RCB (Fisher exact p-value 0.0036 and 0.014 respectively); BIPS score and 3 year RFS logrank p-value <0.001). Specifically, for poor-BIPS-score patients, pCR or RCB status at time of surgery was highly predictive for RFS (p<0.001), where RCB0 and RCBI patients had a 3-year likelihood of RFS of 85%, RCBII 50%, and RCBIII 0% respectively. ER-positive patients comprise a considerable proportion of poor-BIPS patients (20%). Interestingly, each of the 8 poor-BIPS-RCBIII patients relapsed within 18 months and only 17% of triple negative patients fall into this group. Conclusions: Having residual disease after neo-adjuvant chemotherapy has different implications for RFS in the biological context of the tumor. Low risk biology tumors do not seem to benefit from chemotherapy, yet have 3-year excellent outcome. Patients with residual disease in the context of high risk biology clearly need more effective systemic therapy. View this table: Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2003.