Hunt, KK

PURPOSE Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy–proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

Abstract Purpose: To evaluate prediction of response and event-free survival (EFS) following neoadjuvant endocrine therapy by SET2,3 index of nonproliferation gene expression related to estrogen and progesterone receptors adjusted for baseline prognosis. Experimental Design: A correlative study was conducted of SET2,3 measured from gene expression profiles of diagnostic tumor (Agilent microarrays) in 379 women with cStage II–III breast cancer from the American College of Surgeons Oncology Group Z1031 neoadjuvant aromatase inhibitor trial SET2,3 was dichotomized using the previously published cutoff. Fisher exact test was used to assess the association between SET2,3 and low proliferation at week 2–4 [Ki67 ≤ 10% or complete cell-cycle arrest (CCCA; Ki67 ≤ 2.7%)] and PEPI-0 rate in cohort B, and the association between SET2,3 and ypStage 0/I in all patients. Cox models were used to assess EFS with respect to SET2,3 excluding cohort B patients who switched to chemotherapy. Results: Patients with high SET2,3 had higher rate of pharmacodynamic response than patients with low SET2,3 (Ki67 ≤ 10% in 88.2% vs. 56.9%, P &lt; 0.0001; CCCA in 50.0% vs. 26.2%, P = 0.0054), but rate of ypStage 0/I (24.0% vs. 20.4%, P = 0.4580) or PEPI = 0 (28.4% vs. 20.6%, P = 0.3419) was not different. Patients with high SET2,3 had longer EFS than patients with low SET2,3 (HR, 0.52, 95% confidence interval: 0.34–0.80; P = 0.0026). Conclusions: This exploratory analysis of Z1031 data demonstrated a higher rate of pharmacodynamic suppression of proliferation and longer EFS in high SET2,3 disease relative to low SET2,3 disease. The ypStage 0/I rate and PEPI = 0 rate were similar with respect to SET2,3.

Abstract Background: Locoregional recurrence (LRR) is a concern after neoadjuvant chemotherapy. Absolute risk of LRR and risk factors associated with LRR among women with node positive breast cancer treated with neoadjuvant chemotherapy on ACOSOG Z1071 were examined. Methods: ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) enrolled cT1-3, N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009-2011. All patients underwent axillary dissection. Data was analyzed for locoregional recurrence-free survival (LR-RFS) and multivariable analysis performed to identify factors impacting locoregional recurrence. Results: Of 756 women enrolled, 701 patients were eligible. Median follow-up was 4.0 years (range 0.03–6.2). 39 pts (5.6%) experienced LRR (32 LRR alone and 7 LRR concurrent with metastatic disease) and 96 patients (13.7%) died. LR-RFS was lowest in patients with triple negative tumors (TNBC) (87.6% at 3 years), followed by HER2-positive tumors (94.1%) compared with Hormone Receptor (HR) positive/HER2-negative tumors (96.9%). Residual in-breast disease was present in 57% of patients undergoing BCT and 73% of patients undergoing mastectomy (p&lt;0.0001). LRR was higher in BCT compared to mastectomy (p=0.018), however when evaluated by subtype there was no significant difference in LRR by BCT vs mastectomy. There was no difference in LRR by clinical T stage at presentation or pathologic N stage, however LRR increased with higher pathologic T stage (p=0.006). Overall LRR was lower in patients who achieved a pathologic complete response (pCR) across all tumor subtypes (0% in HR positive/HER2-negative, 2.1% in TNBC, 4% in HER2-positive at 3 years) than in non-pCR patients (HR=0.37, p=0.04). By tumor subtype, pCR was associated with a lower LRR in patients with TNBC (HR=0.17, p=0.019), but was not significantly different by pCR in HER2-positive (HR=0.50, p=0.31) or HR-positive/HER2-negative tumors (HR=inestimable). In the multivariable model, factors associated with increased LRR risk were tumor subtype (TNBC and HER2-positive tumors, p&lt;0.0001), lack of pCR in the breast (p=0.013), breast conservation surgery (p=0.018) and omission of adjuvant radiation therapy (p=0.010). Predictors of locoregional recurrence UnivariableMultivariableVariableHR (95% CI)p-valueHR (95% CI)p-valueClinical T stageT0-T2REF0.34REF0.087T3-T41.38 (0.72-2.65) 1.87 (0.91-3.84) Tumor BiologyHR+/Her2-REF0.002REF&lt;0.0001Her2+1.49 (0.65-3.45) 2.11 (0.89-5.00) Triple negative3.59 (1.68-7.68) 5.53 (2.53-12.13) Path CR breastNoREF0.019REF0.013Yes0.35 (0.15-0.84) 0.27 (0.09-0.76) Path CR breastNoREF0.064REF0.81Yes0.51 (0.25-1.04) 0.67 (0.29-1.59) SurgeryBCTREF0.067REF0.018Mastectomy0.55 (0.29-1.04) 0.43 (0.22-0.87) RadiationYesREF0.033REF0.010No2.18 (1.06-4.48) 2.60 (1.26-5.39) Conclusion: In patients with node-positive breast cancer treated with neoadjuvant chemotherapy, early LRR is higher in TNBC and HER2-positive tumors. In TNBC patients pCR is associated with lower LRR than residual disease. In this contemporary cohort of node-positive, HER2-positive tumors treated with anti-HER2 therapy, patients achieving a pCR had low LRR rate. Adjuvant radiation appears to be important for locoregional control regardless of pCR. Citation Format: Boughey JC, Ballman KV, McCall LM, Mittendorf EA, Hunt KK. Predictors of locoregional recurrence after neoadjuvant chemotherapy and surgery for node positive breast cancer: Results from ACOSOG Z1071 (Alliance) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-01.

Abstract Purpose: Emerging data from cooperative group trials suggests that not all patients with a positive SLN require completion axillary lymph node dissection (ALND). The controversy regarding who will benefit from additional nodal clearance continues, suggesting a need for improved tools to predict non-SLN involvement. We hypothesized that the size of a SLN metastasis evaluated as a continuous variable would be an important predictor of non-SLN involvement. The goal of this study was to determine clinicopathologic factors including SLN metastasis size that predicted non-SLN involvement and to use these factors to construct an improved predictive nomogram. Methods: Using a prospective database, we identified 509 patients with invasive breast cancer from 1996 - 2007 with a positive SLN who underwent ALND. Patients receiving neoadjuvant therapy were excluded. Clinicopathologic data including age, primary tumor size, presence of multifocal disease, histology (invasive ductal vs. invasive lobular vs. mixed invasive), tumor grade, estrogen receptor, progesterone receptor, and HER2/neu status, presence of lymphovascular invasion (LVI), the number of SLNs identified, number of positive SLNs, the maximum SLN metastasis size and the presence of extranodal extension were recorded. For SLNs described only as containing isolated tumor cells, size was recorded as 0.1 mm. Univariate and multivariate logistic regression analyses were performed to identify factors predictive of positive non-SLNs. Using these variables, a nomogram was constructed and subsequently validated using an external cohort of 464 patients. Results: On univariate analysis, the following factors were predictive of positive non-SLNs: number of SLN identified (p&lt;.001), number of positive SLN (p&lt;.001), maximum SLN metastasis size (p&lt;.001), extranodal extension (p&lt;.001), primary tumor size (p=.001), LVI (p=.019) and histology (p=.034). On multivariate analysis, all factors remained significant at the 5% level except LVI. A nomogram was created using these variables. When applied to an external cohort, the nomogram was accurate and discriminating with an area under the receiver operating characteristic curve of .73 (95% CI: .68 - .77). Conclusions: SLN metastasis size is predictive for identifying additional disease in the axilla. These data have been incorporated into a nomogram that accurately predicts the likelihood of having additional, non-SLN metastasis suggesting that routine reporting of the SLN metastasis size would assist with clinical decision making regarding the need to perform a completion ALND. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-08.