Introduction Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

The purpose of this study was to assess the prognostic impact of age in patients with triple-negative breast cancer (TNBC). 1,732 patients with primary TNBC were analyzed. Five age cohorts (≤30, 31-40, 41-50, 51-60, and >60 years) at diagnosis were correlated with clinical/pathological parameters. Univariate and multivariate analyses were used to examine the effect of age on disease-free (DFS), distant disease-free (DDFS), and overall survival (OS). In patients with TNBC, increasing age at diagnosis was inversely correlated with tumor grade (P < 0.0001); likelihood of being non-Caucasian (P = 0.0001); likelihood of getting chemotherapy (P < 0.0001); and positively correlated with DFS (P = 0.0003); DDFS (P < 0.0001); and OS (P < 0.0001). The median DFS for patients 31-40 and older than 60 years was 4 years [95 % confidence interval (95 % CI) 2-5] and 8 years (95 % CI 5-14, respectively, P = 0.0003). The DDFS and OS were also statistically significantly shorter for younger patients. In multivariate analysis, tumor size, nodal stage, tumor grade, and age remained significant independent prognostic variables. Clinical characteristics of TNBC differ by age group, patients ≤40 years have poorer survival despite more aggressive systemic therapy.

Background: Trastuzumab and pertuzumab have been shown to work by inhibiting the intracellular signaling linked to HER2 receptor activation, and cytotoxic immune mechanisms, including Fc-dependent immune cell activation. ER+ and ER−/HER2+ breast cancers (BC) are considered molecularly distinct entities (Bianchini G, ASCO 2011; Iwamoto T, ESMO 2012). Regardless of the ER status, immune gene signatures are prognostic and predictive of chemotherapy response (Iwamoto T, ESMO 2012). The gene expression profiles of pre-treatment tumor samples from patients of the NeoSphere trial of neoadjuvant pertuzumab+trastuzumab ± docetaxel (T) (Gianni L, Lancet Oncol 2012) were characterized. We assessed the association of pre-selected adaptive immune functions and key immune regulatory genes with the likelihood of achieving a pathological complete response (pCR) in NeoSphere. Methods: Baseline core biopsies were collected from 387/417 patients. Gene expression profiles (Affymetrix U133 Plus 2.0) were obtained for 367 samples (88% of all patients) that were evenly distributed among arms A (TH, n=90), B (THP, n=95), C (HP, n=98), and D (TP, n=84). ER status was defined by IHC. The primary endpoint was pCR in breast. We assessed metagenes (average expression of the associated genes) corresponding to: immunoglobulins (IgG), CD8A, MHC type I and type II (MHC1, MHC2), interferon inducible genes (I-IG) and STAT1-related genes. We also assessed the individual genes PD1, PD-L1, PD-L2, CTLA4, IFNG. Results: ER+ and ER− tumors had differential mRNA expression for: CD8A, IgG, PD-L2, PD1, IFNG (overexpressed in ER−), and I-IG (overexpressed in ER+). Positive correlations were observed between most of these biomarkers. Only PD1 was inversely correlated with STAT1, interferon and MHC2. In logistic univariate regression analyses some biomarkers showed moderate association with pCR or residual disease without consistent patterns between treatment arms. However, a multivariate logistic regression model constructed for all the selected biomarkers revealed that high expression of PD-L1 was consistently associated with lower pCR rate in all chemotherapy containing arms (A, B and D). A similar trend was present also in Arm C, the arm with antibody treatment alone. In all arms, high expression of IFNG and/or STAT1 were associated with higher pCR rate. In multivariate analysis PD-L1, PD1 and STAT1 were associated with pCR irrespective of the ER status in combined arms A, C and D. In arm B, both CTLA4 and PD-L1 were independently associated with lower pCR in ER− tumors. Conclusions: The association between pCR and selected immune biomarkers in patients treated with pertuzumab, trastuzumab, or both, with or without chemotherapy, supports our understanding of the key role of the immune system in contributing to HER2-targeted antibody therapy on top of signaling inhibition. High PD-L1 expression emerged for its consistent association with lower pCR. These results provide a rationale for combining HER2-targeted treatments with immune-modulating agents and may allow the prediction of treatment benefit. Validation of these results with different assays is ongoing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-7.

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Background: In 2007 we described residual cancer burden (RCB) as a measure of pathologic response after neoadjuvant chemotherapy and demonstrated that RCB was strongly prognostic for 5-year survival outcomes. Herein, we update the long-term outcome of this original cohort, validate our results in an independent patient group, and report outcome according to hormone receptor (HR) and HER2 receptor status. Methods: Our original RCB development cohort received paclitaxel followed by fluorouracil, doxorubicin and cyclophosphamide (T/FAC) and the original validation cohort received FAC alone as neoadjuvant chemotherapy for stage II or III breast cancer (JCO 2007;25:4414-22). We subsequently evaluated RCB in 2008 in another independent validation cohort of patients treated with neoadjuvant T/FAC. These patient cohorts were followed up until 2013. The T/FAC cohorts were combined to test RCB within phenotypic subsets of HER2+, HR+/HER2-, and triple receptor-negative breast cancer (TNBC). Pre-defined RCB classes of pathologic complete response (pCR), minimal (RCB-I), moderate (RCB-II) and extensive (RCB-III) residual disease were compared with respect to relapse-free survival (RFS) using the likelihood ratio test and estimates of 10-year RFS (with 95% confidence interval) were determined from Kaplan-Meier analysis. We excluded patients with HER2-positive (HER2+) cancer who received neoadjuvant or adjuvant trastuzumab. Results: Median follow up of event-free survivors was 142 months for the original T/FAC development cohort (N = 220), 91 months for the T/FAC validation cohort (N = 277), and 198 months for the FAC (N = 169) cohort. The estimates of 10-year RFS by RCB class for each cohort, respectively, were 86%, 81% and 95% for pCR; 87%, 81% and 85% for RCB-I; 76%, 62%, and 62% for RCB-II; and 38%, 36% and 38% for RCB-III. Table 1 presents the frequency and the estimates of 10-year RFS for each RCB class within each phenotypic subset of breast cancer (HER2+, TNBC, and HR+/HER2-) in the combined T/FAC cohorts (N = 497). Frequency and estimated 10-year RFS of RCB classes in breast cancer subsets after T/FAC chemotherapy HER2+TNBCHR+/HER2-RCB ClassFreqRFS (95% CI)FreqRFS (95% CI)FreqRFS (95% CI)pCR36%83% (66 to 92)35%82% (63 to 92)10%83% (59 to 93)RCB-I16%69% (41 to 86)15%82% (53 to 94)13%96% (74 to 99)RCB-II30%50% (31 to 66)33%54% (38 to 68)60%76% (68 to 83)RCB-III18%32% (13 to 52)17%18% (6 to 36)17%45% (27 to 61)RFS, relapse-free survival; Freq, frequency; CI, confidence interval. RCB was prognostic in all cohorts and subgroups (p&lt;0.001). The hazard rate (per year) associated with RCB-III and RCB-II was highest during the first 3 years for HER2+ and TNBC but was similar to pCR/RCB-I beyond 6 years. However, for HR+/HER2- cancers the annual hazard rate was consistent during the first decade, at 6%-8% for RCB-III and 2% for RCB-II. Conclusions: RCB after neoadjuvant chemotherapy was strongly prognostic in all phenotypic subsets of breast cancer patients over a decade of follow up, even for HR+/HER2- cancers. In HER2-negative breast cancers, RCB-I had similar prognosis to pCR, whereas RCB-III for HR+/HER2- and RCB-II/III for TNBC defined high-risk patient populations following neoadjuvant chemotherapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-02.