Boughey, Judy C.

Abstract Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility (<10% probability of success), maximum sample size accrual (10% <probability of success <85%), or safety as recommended by the independent DSMB. Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-02.

Abstract Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

Abstract Background: Recent studies have demonstrated independent validation of the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. However, a pooled subject-level analysis of multiple cohorts is needed to determine estimates of long-term prognosis for each class of RCB in each phenotypic subtype of breast cancer (BC) to better inform on patient outcomes. Also, a pooled subject-level analysis allows more detailed analyses of generalizability of the prognostic meaning of RCB assessments in a broader experience of practice settings. Method: Subject-level RCB results, with relevant clinical and pathologic stage, tumor subtype and grade, demographic, treatment and follow-up data from 11 institutes/trials are being collected for combined analysis. The association between the continuous RCB index and event-free survival (EFS), and distant recurrence free survival (DRFS) were assessed using mixed effect Cox models with the incorporation of random RCB coefficients to account for between-study heterogeneity. We will also allow for differences in baseline hazard across biological BC subtypes and, if needed, across studies as well. In addition to this stratified mixed effect model, a multivariate analysis adjusting for age, T-category, nodal status and grade was performed within each subtype. In addition, mixed effect Cox models will be employed to evaluate association between RCB index with EFS and DRFS within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at 5 and 10 years were computed for each RCB class within subtype. Results: We analyzed subject-level data from 9 institutes/trials representing 4077 patients currently available from an anticipated final total of 4,800 patients (to be presented at the meeting). There were 950 EFS and 876 DRFS events during follow up (median 65 months, IQR: 70 months). RCB index (continuous) was independently prognostic within each subtype: HR+/HER2- (EFS HR (per unit increase in RCB index) =1.64, 95%CI 1.48-1.82; DRFS HR=1.68, 1.51-1.87), HR+/HER2+ (EFS HR=1.80, 1.57-2.05; DRFS HR=1.93, 1.67-2.24), HR-/HER2+ (EFS HR=2.15, 1.76-2.62; DRFS HR=2.10, 1.77-2.50), and HR-/HER2- (EFS HR=2.05, 1.89-2.22; DRFS HR=2.16, 1.90-2.46); and remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis. Table 1 contains the response rate and estimated EFS at 5 years and 10 years for each RCB class within each HR/HER2 phenotype (DRFS results were similar). Conclusions: Long-term prognosis after pCR was similarly excellent in all phenotypic subtypes. RCB index and classification was independently and strongly prognostic in all subtypes, and generalizable to multiple practice settings. Prognostic differences by RCB class occurred within 5 years in HR- BC, but extended to 10 years in HR+ BC. RCB-I had slightly worse EFS than pCR in HR- BC and HR+/HER2+ BC (after 5 years), but the same EFS as pCR in HR+/HER2- BC. Complete analysis of all subjects, including neoadjuvant treatments, will be presented at the meeting. PhenotypeOutcomepCRRCB-IRCB-IIRCB-IIIHR+/HER2-Frequency (%)11%10%52%27%(N=1467)5 yr EFS (95% CI)91% (86-96)93% (89-98)82% (79-85)70% (65-75)10 yr EFS (95% CI)84% (75-93)88% (82-95)71% (67-75)52% (46-58)HR+/HER2+Frequency (%)38%18%35%9%(N=762)5 yr EFS (95% CI)94% (91-97)93% (88-98)78% (73-84)49% (37-65)10 yr EFS (95% CI)91% (86-96)79% (70-90)65% (59-73)42% (29-60)HR-/HER2+Frequency (%)66%11%18%5%(N=550)5 yr EFS (95% CI)93% (90-96)88% (79-97)60% (50-71)45% (30-69)10 yr EFS (95% CI)90% (86-94)84% (74-95)56% (46-68)45% (30-69)HR-/HER2-Frequency (%)41%13%33%13%(N=1293)5 yr EFS (95% CI)92% (90-94)85% (79-91)68% (63-72)28% (21-36)10 yr EFS (95% CI)87% (82-91)80% (72-88)63% (58-68)24% (18-33) Citation Format: Christina Yau, Marieke van der Noordaa, Jane Wei, Marie Osdoit, Fabien Reyal, Anne-Sophie Hamy, Marick Lae, Miguel Martin, Maria del Monte, I-SPY 2 TRIAL Consortium, Judy C Boughey, Rebekah Gould, Jelle Wesseling, Tessa Steenbruggen, Maartje van Seijen, Gabe Sonke, Stephen Edge, Stephen-John Sammut, Elena Provenzano, Jean Abraham, Peter Hall, Ashley Graham, Lorna Mackintosh, David Cameron, Alice Wang, Priyanka Sharma, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura van ‘t Veer, Laura Esserman, W. Fraser Symmans. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-01.

Abstract Importance: It is essential to refine the populations most likely to benefit from targeted chemotherapy combinations. Background: MINDACT showed that molecularly low risk patients, as assessed by the Amsterdam 70-gene profile MammaPrint® (Agendia) (MP), did not benefit from chemotherapy. In the I-SPY2 trial, MP low risk Hormone Receptor (HR) positive/HER2 negative patients are not eligible; however, HR negative or HER2 positive patients were considered high risk and included for treatment with chemotherapy plus novel agents. The neoadjuvant setting provides an opportunity to evaluate whether molecularly low risk HER2 positive patients are good candidates for neoadjuvant chemo/anti-HER2 therapy, where pathologic complete response (pCR) and 3-year outcomes are measured. Objective: To evaluate and further characterize the fraction of and outcomes for patients molecular low-risk disease in the I-SPY2 trial. Methods: The I-SPY2 platform trial is an ongoing multicenter phase 2 multi-arm study utilizing adaptive design and evaluating efficacy and tolerability of investigational agents in combination with standard-of-care chemotherapy for patients with high-risk anatomic stage II/III breast cancer. Patients with HR+HER2- MP low-risk tumors are not eligible. All enrolled patients undergo pretreatment biopsy for genomic evaluation of early recurrence risk with MP for risk stratification and with the 80-gene BluePrint® (Agendia) test for intrinsic subtype classification. Primary endpoint of the study is pCR in breast and lymph nodes (ypT0/is, ypN0). Secondary outcomes included event-free survival (EFS) and distant-recurrence free survival (DRFS). Following standard neoadjuvant treatment with or without a concomitant investigational agent, patients are followed for long-term outcomes. EFS and DRFS at 3 and 5 years in the pCR vs non-pCR groups within histologic and molecular subtypes are determined using the Kaplan Meier method. Results: Of the 1038 enrolled patients by November 2016, 24 patients (3.2%) had molecular low-risk disease as determined by MP. Of these, 21 (87.5%) had HR+HER2+, 1 (4.2%) had HR-HER2+, and 2 (8.4%) had HR-HER2-. BluePrint expression subtyping classified 17 as luminal-type, 6 HER2 enriched-type and 1 basal type. One patient withdrew consent for follow-up. Of the 23 remaining, none achieved pCR and only one (HR+/HER2+) had an EFS event (with median follow-up of 4.3 years). Overall, EFS and DRFS data were available for 950 of the 1038 patients (as of February 2019), with median follow-up of 3.8 years. Of the 173 HR+HER2+ in this cohort, 20 (11.6%) had molecular low-risk tumors. The EFS and DRFS for the 173 HER2+HR+ pCR group is 97% and 98% (non-pCR group 89% and 94%), respectively at 3 years. Removing the molecular low-risk HER2+ patients from the denominator reveals the worse outcome for patients with non pCR: EFS 86% and DRFS 92% at 3 years. The difference is more apparent at 5 years, changing from 74% to 66% for EFS and from 81% to 75% for DRFS. Intrinsic subtypes vary and do not predict early risk. Conclusions: I-SPY2 focuses on women with high clinical risk with only 3.2% of enrolled patients having low molecular risk tumors. However, 12% of HER+ breast cancer enrolled patients had molecular low risk tumors of which 95% were also HR+. In this group, early recurrence is very low despite absence of pCR and irrespective of intrinsic subtype. Refining the population using molecular high-risk classification of patients reveals a greater difference between the pCR and non-pCR groups within the HR+HER2+ subtype in the EFS and DRFS analysis. Clinical trial designs could address the opportunity to find more targeted and less toxic treatments for the HER2+ low molecular risk patient population. Citation Format: Paula R Pohlmann, Christina Yau, Angela DeMichele, Claudine Isaacs, Judy C Boughey, Nola Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, W. Fraser Symmans, I-SPY 2 TRIAL Consortium, Donald A Berry, Laura Esserman. Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-06.

526 Background: Z1041 randomized women with HER2+ operable breast cancer to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2). Treatment administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2weekly x 12 and T 4 mg/kg once then 2 mg/kg weekly x 11. T was to continue q3 weeks post-op for 40 weeks. A secondary aim was to examine the cardiotoxicity (CE). Methods: Ejection fraction (EF) was measured at baseline (BL), between regimens (wk 12), prior to surgery (wk 24) and PRN. Eligibility: BL EF ≥ 55%. CEs included decline in EF of > 15%, or >10% points to a value < LLN. Reversibility was adjudicated by blinded investigators as reversible (R: recovery of EF to ≤ 5% below BL), partially reversible (PR: recovery of > 10% points from nadir, but ≤ 5% points below BL), indeterminate (IN: no additional EF data), or irreversible (IRR:follow-up EF studies showed no improvement). Results: Of the 280 patients (Arm 1: 138) who began treatment, 15 pts (Arm 1: 10; Arm 2: 5) did not receive T. The number of weeks of T was 13 (range: 1-18) in Arm 1 and 24 (range: 1-31) in Arm 2. Changes in EF and severe treatment related cardiac toxicities prior to surgery (sx) are tabled below. There were 271 pts (Arm 1: 131) who had post-BL EFs. Prior to sx, there were 11 CE (8.3%) in Arm 1 and 13 CE (9.2%) in Arm 2. CEs were R in 12 pts (Arm 1: 5; Arm 2: 7); PR in 6 pts (Arm 1: 4; Arm 2: 2); IN in 4 pts (Arm 1: 2; Arm 2: 3) and IRR in 1 Arm 2 pt. Conclusions: The number of CE events in arms 1 and 2 showed no significant difference; greater scatter was observed in arm 2 patients. While concern for late cardiac events makes ongoing cardiac surveillance prudent due to A, concomitant use of A and T appear to not be associated with increased cardiac risk. Clinical trial information: NCT00513292. [Table: see text]

507 Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER+ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n=112); B: mets within 3 months of primary surgery (n=16)). This study includes 110 pts with pre-treatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER+, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS<18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RS≥31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER+ pts and for 2 yr OS in ER+Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER+ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p=0.003) and for OS in ER+Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p=0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER+ pts (p=0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER+ Stage IV BC. RS is also prognostic for OS in ER+Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER+ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. [Table: see text]

502 Background: Neoadjuvant chemotherapy (NAC) and concomitant trastuzumab (T) have produced high pathologic complete response (pCR) rates in HER2+ breast cancers. Z1041 addresses the timing of initiation of T with NAC. Methods: Women with operable HER2+ invasive breast cancer were randomized 1:1 to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4 (FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. Eligibility also included: tumor > 2 cm or a positive lymph node and left ventricular ejection fraction > 55%. The primary aim was to compare the pCR rates in the breast (pBCR) between the regimens. Secondary endpoints were pCR rate in the breast and lymph nodes (pBNCR) and safety profile. All pts who began study treatment were included in the analyses. With 128 pts per regimen, a two-sided alpha=0.05 test of proportions would have a 90% chance of detecting a difference of 20% or more in the pBCR rates, when the pBCR rate with the poorer regimen is ≤ 25%. Results: From September 15, 2007 to December 15, 2011, 282 women (Arm 1: 140 pts) were enrolled. Two pts (Arm 1) withdrew without receiving treatment. The two arms were similar in age, stage, and hormone receptor (HR) status (HR neg: 40%). The severe (grade 3+) treatment-related toxicities included: neutropenia (Arm 1: 24.6%; Arm 2: 32.4%), fatigue (Arm 1: 4.3%; Arm 2: 8.5%), and neurosensory problems (Arm 1: 3.6%; Arm 2: 4.9%). The pBCR rate and pBNCR rates (Table) were not found to differ between the two regimens (Fisher’s exact p values: 0.905 and 0.811, respectively). Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes. The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab. Clinical trial information: NCT00513292. [Table: see text]

1107 Background: The role of axillary ultrasound (AUS) after neoadjuvant chemotherapy (NAC) to assess for residual nodal disease in patients presenting with node positive breast cancer remains unclear. ACOSOG Z1071 is a prospective multi-institutional trial evaluating sentinel node biopsy in patients with biopsy proven node positive breast cancer (T0-4, N1-2, M0) receiving NAC. Herein we report on the secondary objective evaluating the correlation of lymph node (LN) features on AUS with residual nodal disease. Methods: AUS images from diagnosis and after NAC were centrally reviewed for cortex size, LN size and LN morphology. Morphologic features were defined as: type I, no visible cortex, type II, < 3 mm hypoechoic cortex, type III, > 3mm hypoechoic cortex, type IV, generalized lobulated hypoechoic cortex, type V, focal hypoechoic cortical lobulation, and type VI, totally hypoechoic node with no hilum. Type I and II are considered normal. Results: Surgical and imaging data are available on 294 patients. Median age was 50 years (range 23-93 years), mean initial tumor size 3cm (0 to 15cm) and clinical stage II in 64.5% and III in 35.5%. The maximum LN diameter decreased after NAC (mean 22mm pre-NAC to 14mm post-NAC)(p<0.0001); however, there was no significant difference after NAC between the pathologically N+ (13mm, range 5-46mm) and N0 cases (12mm, range 3-32mm)(p=0.13). LN cortical thickness correlated with residual nodal disease after NAC (p-value = 0.04). Using a cutoff point of cortical thickness of 3 mm, the sensitivity was 33% (48/145) and specificity 80% (66/82). AUS morphological features after NAC was associated with false negative rate 62%, false positive rate 28%, sensitivity 38%, and specificity 72%. Conclusions: AUS after NAC is useful to assess nodal response. Cortical thickness was the best predictor of residual nodal metastasis. LN size and morphological features do not reliably exclude residual nodal metastasis in patients after NAC. [Table: see text]

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.