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Introduction Recent advances in breast cancer treatment strategies have improved survival outcomes in metastatic breast cancer (mBC). Targeting immune checkpoint, especially programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), has made a breakthrough in treating advanced malignancies including breast cancer. Immune checkpoint inhibitors (ICIs), such as pembrolizumab and atezolizumab, in combination with chemotherapy have prolonged survival outcomes in mBC with triple negative subtype. However, the low response rate and resistance of ICIs with anti-PD 1/PDL-1 antibodies is a major limitation and a challenge. Lymphocyte Activation Gene-3 (LAG3; CD223) is a potential cancer immunotherapeutic target due to its negative regulatory role on T cells and cytokines, thereby ensuring immune homeostasis. Several studies suggested that combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown promising efficacy in fighting PD-1 resistance. Therefore, we evaluated the prognostic role of LAG3 in metastatic TNBC (mTNBC) treated with ICIs to figure out resistance mechanism of ICIs. Methods mTNBC patients with available archival tumor tissues, who has received ICIs in Samsung Medical Center, were enrolled in this study. For the evaluation of LAG3 expression in tumor microenvironment, Vectra Polaris Multispectral Imaging and Whole Slide Scanning technique (PerkinElmer, Inc. Hopkinton, MA) was used. Results In total, 64 mTNBC patients were treated with ICI’s with or without cytotoxic chemotherapy between 2019.02- 2021.11. Of 70 mTNBC patients, 41 patients had archival tissues and finally 40 patients were included in this study. Median age was 43.0 years of age (range: 24.5 ~ 64.5). Recurrent mTNBC was 92.5% and only 7.5% was de novo mTNBC. Geremline BRCA1 pathogenic variants were detected in 4 (10.0%) patients. Among 37 recurrent mTNBC patients, 72.5% were treated with neoadjuvant chemotherapy with anthracycline (97.3%) and taxane(97.3%). Among ICI’s, 52.5% were treated with pembrolizumab and 47.5% of atezolizumab. LAG3 expression varies among mTNBC tissues (median cell density: 366, range: 48, 2861 cells/mm2). Among cells expressing LAG3, LAG3 was expressed more in CK+ cells compared with CK- cells (median:150 (20, 2503) cells/mm2 in CK+ cells, median: 88 (2, 806) cells/mm2 in CK- cells, p=0.005). Patients with high LAG3 expression in CK+ cells showed short progression free survival(PFS) compared to those with low LAG3 expression in CK+ cells (median PFS of high vs. low LAG3 expression [months]:1.9 vs. 4.2, p=0.01). On the contrary, patients with high LAG3 expression in CK- cells had 9.1 months of PFS compared to 3.1 months of PFS in patients with low LAG3 expression in CK- cells (p=0.10). In addition, patients with high LAG3 in CK- cells had longer overall survival(OS) compared to those with low LAG3 expression in CK- cells (median OS of high vs. low LAG3 expression [months]: not reached, 15.7, p=0.05). Conclusion LAG3 expression was associated with PFS in patients with mTNBC treated with ICI’s independent of PDL-1 expression. And the prognostic significance of LAG3 expression was different between CK+ cells and CK- cells. These findings need to be proved in large scale clinical trials. Citation Format: ji-Yeon Kim, Jeehyun Kim, Hae Hyun Jung, eun Yoon Cho, Yeon Hee Park, Jin Seok Ahn, Kyoung-Mee Kim, Young-Hyuck Im. Prognostic impact of lymphocyte-Activation Gene-3 (LAG-3) expression in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-10.

Background: Neutrotrophin receptor tyrosine kinase (NTRK) gene fusions (NTRK1, NTRK2, or NTRK3) are oncogenic drivers of various tumor types. The NTRK fusion was detected in less than 5% of breast, colorectal, lung or any other types of cancers. However, large scaled next generation sequencing data for NTRK fusion in breast cancer have not existed. In this study, we performed RNASeq and fusion analysis including NTRK genes. Methods: We prospectively collected BC tumor tissues from the translational research conducted in Samsung Medical Center. Fusion was predicted from RNAseq using the following seven softwares(SWs): ChimeraScan, DeFuse, MapSplice, TophatFusion, STAR.Arriba, STAR.fusion, and STAR.SEQR. To remove false-positive fusion calls, calls less than 3 left/right spanning reads and 10 total supporting reads were removed. After filtering out the blacklist fusion calls which were recurrently detected, calls commonly predicted in more than two SWs were analyzed. Results: In total 629 BC samples, 613 samples were finally analyzed after quality control (QC) of RNASeq. According to immunohistochemistry (IHC) profile, 356(58.7%) was hormone receptor (HR) positive human epidermal growth factor receptor 2 (HER2) negative BC, 42 (6.9%) of HR positive HER2 positive BC, 53 (8.7%) of HR negative, HER2 positive and 155(25.6%) of triple negative BC (TNBC). PAM50 prediction informed that 174(28.9%) of luminal A, 151(24.6%) of luminal B, 170 (27.7%) of basal-like, 85 (13.9%) of HER2-enriched and 33 (5.4%) of normal. In median number of fusion events, 12 was called by ChimeraScan (Interquartile range [IQR]: 5, 33), 57 by DeFuse (IQR: 33, 82), eight by Mapsplice (IQR: 5, 12), two by TophatFusion (IQR: 0, 4), five by STAR.Arriba (IQR: 2, 12), two by STAR.fusion (IQR:0, 5) and three by STAR.SEQR fusion caller (IQR: 1, 7) after call filtering. After initial fusion call, we excluded the results from ChimeraScan and DeFuse fusion callers because of discrepancy of number of called fusion events. In five fusion callers, median number of fusion events was eight (IQR :2,20) per BC sample. In terms of NTRK fusion, we detected NTRK2-BANCR fusion event in one TNBC patients (1/425, 0.2%). This fusion was detected in four of five SWs for fusion detection with significant number of supporting reads in RNASeq. NTRK2-BANCR fusion was the out-of-frame fusion, which C-terminal truncated protein kinase domain of NTRK2 and its partner long non-coding RNA BANCR was combined and RNA expression of this fusion was increased. Other fusion events of BCs were NCOR2-PARP4 (3.7%), BRD4-NWD1 (3.7%), ESR1-RGS17 (1.8%), FGFR1-TACC1 (0.2%) and MKRN1-BRAF (0.2%). In BC subtype according to IHC, fusion events were more frequently observed in TNBC compared with other subtypes regardless of the type of fusion filters. In terms of intrinsic subtype, fusion events were most frequently observed in basal like type and least in normal like intrinsic subtype (all ps Citation Format: Ji-Yeon Kim, Kyunghee Park, Woong-Yang Park, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Jonghan Yu, Young-Hyuck Im, Jin Seok Ahn, Yeon Hee Park. Fusion analysis including NTRK fusion in breast cancers (BC): From RNASeq data analysis from 629 BC tissue samples [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-08.

Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-08.

Introduction Adding pertuzumab(P) on trastuzumab(H) with cytotoxic chemotherapy increased pathologic complete response (pCR) of early or locally advanced HER2 positive breast cancer (EBC) with neoadjuvant chemotherapy. Since 63.6% of pCR rate has been reported from TRYPHAENA trial, TCHP regimen has been used as a standard of neoadjuvant treatment regimen for patients with HER2 positive EBC. However, this regimen has profound toxicities in terms of myelosuppression, neurotoxicity, and etc. Furthermore we still need more information on clinical outcomes and toxicities with this regimen. Therefore, we report real world experience of EBC patients treated with neoadjuvant TCHP followed by curative surgery. Methods We retrospectively reviewed electronic medical record of EBC patients who received neoadjuvant TCHP. Information which we gathered included patients’ and tumor characteristics at the time of diagnosis, details of neoadjuvant chemotherapy, pathologic assessment of tumor response to neoadjuvant TCHP and recurrence free survival after curative surgery. pCR was defined as absence of residual invasive cancer on pathologic evaluation of the resected breast specimen and all sampled regional lymph nodes (ypT0/isN0). Results Between February 2016 and August 2019, 447 patients were treated with neoadjuvant TCHP followed by curative surgery. Median age at BC diagnosis was 56. In clinical stage, stage II was 54.6% and 45.4% of stage III and hormone receptor (HR) positive BC was 48.3%. Most commonly reported adverse event(AE) was mucositis (84%) followed by diarrhea (77%). In terms of Grade 3 AE, anorexia(6%), diarrhea(2%) were frequently observed and 9(2%) of febrile neutropenia occurred despite of prophylactic use of peg-filgrastim. Forty percent of patients experienced dose reduction due to AEs. Of 447 patients, 29% of patients underwent total mastectomy and 71% of breast conserving surgery. In terms of clinical outcome, pCR rate was 64%; 77% of HR negative BCs and 50% of HR positive BCs. Among baseline characteristics, high nuclear grade, high histologic grade, HR stats affected to pCR status (Ps Key words: neoadjuvant chemotherapy, HER2+ breast cancer, pertuzumab, pathologic complete response Citation Format: Ji-Yeon Kim, Seok Jin Nam, Seok Won Kim, Jonghan Yu, Byung Joo Chae, Se Kyung Lee, Jai Min Ryu, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park. Real Would Evidence (RWE) of neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in patients with HER2 positive early or locally advanced breast cancer treated Single institutional experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-38.

Background: Margetuximab (M) is an investigational Fc-engineered, anti-HER2 monoclonal antibody with the same epitope specificity as trastuzumab (T). Relative to T, Fc engineering of M increases binding affinity for the activating Fc receptor (FcR) CD16A and decreases affinity for the inhibitory FcR CD32B. The SOPHIA trial (NCT02492711) randomized pretreated HER2+ MBC patients to either M or T, each with chemotherapy (C). M+C improved progression-free survival (PFS) benefit over T+C. Infusion related reactions (IRR) have been observed after infusion of therapeutic proteins, typically during the first infusion, with a first-dose incidence of up to 40% for T (Herceptin Prescribing Information®). A retrospective analysis of 197 patients showed 16% IRRs on T, mostly after the first infusion; this rate was lower with (10%) compared to without (19%) premedication (Thompson, 2014). Here, we report IRR safety and tolerability data in the SOPHIA trial patients following HER2-targeted antibody therapy. Methods: The open-label Phase 3 SOPHIA trial enrolled patients with HER2+ MBC after at least 2 prior anti-HER2 therapies, including pertuzumab; 91% in both groups also received ado-trastuzumab emtansine. Randomization of 536 patients was 1:1 to M (15 mg/kg IV q3w) or T (6 [8 loading dose] mg/kg IV q3w), each with Investigator selected C (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). M was given as 120-minute infusions. T was given as a 90-minute infusion in Cycle 1, then a 30-minute infusion from Cycle 2 onward. Recommended elective premedication included acetaminophen, ibuprofen, diphenhydramine, ranitidine, dexamethasone, or equivalents. IRR safety analyses were conducted on 530 patients (264 M+C and 266 T+C) that received any study therapy. Results: A higher proportion of patients experienced IRRs on the M arm (35 [13.3%]) than on the T arm (9 [3.4%]). Most IRRs in both groups were severity Grade 1 or 2, occurred on Cycle 1 Day 1, and resolved within 24 hours. In patients receiving M, Grade 3 IRR occurred in 4 patients (1.5%), including 3 after vinorelbine and 1 after eribulin. Adverse events associated with Grade 3 IRRs included chills, fever, nausea, diarrhea, dyspnea, and/or hypertension. Two patients receiving M (0.8%) discontinued due to IRR, versus none on T. Of patients with IRRs, the most common symptoms in both treatment groups were chills (M: 17 [48.6%]; T: 5 [55.6%]) and fever (M: 13 [37.1%]; T: 2 [22.2%]). There was no observed hypotension in either group. In both groups, more than half of IRR events were addressed by dose interruption only. All IRRs all were medically manageable. IRR rates were higher in patients without premedication for both groups. Of 264 subjects receiving M, 218 (82.6%) received premedication and 46 (17.4%) did not; IRRs were observed in 28 (12.8%) of those receiving premedication and 7 (15.2%) of those not premedicated. All 4 patients on M with Grade 3 IRRs received premedication, 3 with steroids. Of 266 subjects receiving T, 173 (65%) received premedication and 93 (35%) did not; IRRs were observed in 5 (2.9%) of those receiving premedication and 4 (4.3%) of those not premedicated. IRR risk was unaffected by chemotherapy subgroup or CD16A genotype. Conclusions: In the SOPHIA trial, IRR events occurred in a greater proportion of patients on M than on T. Most were mild to moderate in severity, limited to Cycle 1, and resolved on the same day. Symptom patterns were similar between groups, and premedication did not eliminate the hazard of IRRs in either group. Severe IRRs and discontinuations due to IRRs were rare. IRRs on first infusion of M appear to resemble those observed following first infusion of T. Citation Format: Javier Cortes, Fatima Cardoso, Giuseppe Curigliano, William J Gradishar, Seock-Ah Im, Hope S Rugo, Shakeela W Bahadur, Alfredo Falcone, Serafin Morales Murillo, David A Riseberg, Antonino Musolino, Trevor M Feinstein, Miguel H Abreu, Young-Hyuck Im, Yelena Novik, Timothy Pluard, Lupe G Salazar, Rossana Berardi, Viorela Pop, Shengyan Hong, Kenneth Jacobs, Edwin Rock, Mark D Pegram. Infusion related reactions in the phase 3 SOPHIA trial of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with pretreated HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-24.

Introduction: According to phase II clinical trial of endocrine treatment for hormone receptor positive (HR+) metastatic breast cancer(MBC) after tamoxifen treatment in premenopausal women, fulvestrant plus goserelin (F+G) has better clinical outcome than goserelin (G) alone in premenopausal women, in terms of time to progression (TTP). However, aromatase inhibitor (AI) with goserelin (A+G) is not superior to goserelin alone. Among three treatment arms, difference of overall survival (OS) was not observed. Accompanied with this clinical trial, we conducted further genotyping to identify alleles at some genomic loci associated with clinical outcome of endocrine treatments in premenopausal women with HR+ MBC. Methods: This prospective genotyping study included patients enrolled in a randomized phase II clinical trial of fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for HR+, human epidermal growth factor receptor 2(HER2)-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04). To isolate genomic DNA from peripheral blood leukocytes, we used the Wizard Genomic DNA Purification Kit according to the manufacturer’s instructions (Promega, WI) and Axiom Precision Medicine Research Array (PMRA) (ThermoFisher, CA) was used to genotyping array. Survival analyses for time-to-progression (TTP) and overall survival (OS) were performed using the Kaplan-Meier method. To determine the association between clinical outcomes and single nucleotide polymorphisms (SNPs), we used an R package for genome-wide survival analysis (gwasurvivr). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for univariate and multivariate analyses. Finally, SNPs with adjusted p-value Results: Of 138 participants, genomic DNA was collected and extracted from 127 participants. After quality control (QC), 103 genomic DNA were finally selected for genotyping (35 in F+G, 36 in A+G and 32 in G group). Patients with age under 40 were 34 (33%) and visceral metastases were observed in 50 patients (49%). Medial TTP was 16.3 months (95% confidence interval (CI): 13.3, 19.3) and median OS was 59.6 months (95% CI: 41.1, 78.1). Among 523,289 SNPs, 76 SNPs were associated with TTP (adjusted p-value Conclusions: Genetic polymorphisms influenced the clinical outcome of HR+ MBC patients treated with anti-hormonal therapy. Further studies on the functional mechanisms relating to these SNPs in these genes are warranted. Citation Format: Ji-Yeon Kim, Seock-Ah Im, Kyung Hae Jung, Keun Seok Lee, Joohyuk Sohn, Jee Hyun Kim, Hae Hyun Jung, Minjoo Lee, Young-Hyuck Im. Genome-wide association study predict prognosis of hormone receptor positive metastatic breast cancer in premenopausal women with endocrine 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 P3-08-50.

Background: MONALEESA-7 is a Phase III study (NCT02278120) and the only dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 inhibitor in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC). The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended both progression-free survival (PFS; hazard ratio, 0.55; Tripathy D et al. Lancet Oncol. 2018) and overall survival (OS; hazard ratio, 0.71; Im S-A et al. N Engl J Med. 2019). Health-related quality of life (HRQOL) and work productivity are other important aspects of clinical benefit, especially in the premenopausal population. We present analyses of QOL and work productivity from MONALEESA-7. Methods: Premenopausal or perimenopausal patients with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. A secondary endpoint was evaluation of patient-reported outcomes (PROs) for HRQOL using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire core 30 (QLQ-C30). Assessments included global health status as well as social, emotional, and physical functioning. Description of Work Productivity and Activity Impairment (WPAI) was an exploratory endpoint and was measured using the WPAI Questionnaire: General Health (WPAI:GH; V2.0). Results: Time to deterioration (TTD) ≥ 10% in EORTC QLQ-C30 global health status was prolonged with RIB vs PBO (median, 35.8 vs 23.3 months; hazard ratio, 0.665 [95% CI, 0.517-0.855]). TTD ≥ 10% in emotional functioning was also prolonged with RIB vs PBO (hazard ratio, 0.636 [95% CI, 0.488-0.828]), as was TTD ≥ 10% in social functioning (hazard ratio, 0.813 [95% CI, 0.610-1.084]) and TTD ≥ 10% in physical functioning (hazard ratio, 0.715 [95% CI, 0.526-0.972]). Compliance rates with the WPAI:GH were > 99% at baseline and > 98% at the end of treatment. Neither arm had an increase from baseline to the end of treatment in mean percentage of work missed due to overall health. Change in percent activity impairment due to overall health was comparable between treatment arms, as were change in percent impairment while working due to overall health and percent overall work impairment due to overall health. The trends observed with RIB vs PBO in the EORTC QLQ-C30 and WPAI:GH in the overall population were generally similar in the NSAI cohort. Conclusions: WPAI and global health are important considerations in the premenopausal patient population. Analysis of PROs demonstrated that TTD ≥ 10% in global health status and emotional functioning were prolonged with RIB vs PBO. Social and physical functioning were maintained in both treatment arms. Results in various WPAI domains demonstrated that productivity was also maintained in both groups. These QOL and WPAI results, in addition to the significantly longer PFS and OS results with RIB vs PBO, indicate a substantial clinical benefit with RIB treatment in premenopausal patients with HR+/HER2− ABC. Citation Format: Nadia Harbeck, Sara Hurvitz, Aditya Bardia, Fabio Franke, K. Gonvind Babu, Paul Wheatley-Price, Young-Hyuck Im, Kadri Altundag, Antonia Ridolfi, David Chandiwana, Brad Lanoue, Lakshmi Menon, Debu Tripathy. Patient-reported outcomes, including work productivity, from the MONALEESA-7 trial of ribociclib plus endocrine therapy in patients with HR+/HER2− advanced breast cancer [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 P1-19-06.

Background: The APHINITY trial demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (IDFS) among patients with HER2-positive, operable breast cancer. From November 2011 until August 2013, 2400 patients were randomly assigned to receive pertuzumab and 2405 to receive placebo. The clinical cut off-date for the primary analysis was 19 Dec 2016 after a median follow-up of 45.4 months. In the intent-to-treat (ITT) population, the estimates of the 3-year rates of IDFS were 94.1% in the pertuzumab group and 93.2% in the placebo group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The benefit appeared more pronounced in patients with node-positive disease, with a HR of 0.77 (95% CI 0.62-0.96), and in those with hormone receptor-negative disease, where the HR was 0.76 (95% CI 0.56-1.04). Based on these results, pertuzumab in combination with trastuzumab was approved for high risk early HER2-positive breast cancer patients. The first interim analysis of OS took place at that same time. A total of 169 patients had died, with no significant treatment effect with regards to mortality found at that time. Diarrhea, grade 3 or higher, was more frequent within the pertuzumab group (9.8%) compared with the placebo group (3.7%). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Results: At 74.1 months of median follow-up (clinical cut-off date June 19, 2019), we now report results of the pre-planned, calendar-driven second interim OS analysis which requires a p-value of 0.0012 to reach statistical significance. Updated descriptive analyses of IDFS and cardiac safety were also performed. Fewer deaths were observed in the pertuzumab (P) arm [125 (5.2%) vs 147 (6.1%)], however statistical significance was not reached at this interim analysis. The hazard ratio for OS is 0.85 [95% CI 0.67-1.07 (p=0.17)]; 6-year OS percents are 94.8% vs 93.9% (0.9% difference).Updated IDFS results based on 508 events in the ITT population are: hazard ratio 0.76 [95% CI 0.64-0.91]; 6-year IDFS percents are 90.6% vs 87.8% (2.8% difference). Of note, the difference was due mainly to the reduction in distant (5.9% vs 7.7%) and loco-regional (1.2% vs 2.0%) BC relapses. The node-positive cohort continues to derive clear benefit from the addition of P: hazard ratio 0.72 (95% CI 0.59-0.87). The benefit in terms of 6-year IDFS percent is 4.5% [87.9% vs 83.4%].In the node-negative cohort, the IDFS hazard ratio is 1.02 (95% CI; 0.69-1.53) with 95% of patients being event-free in both arms at 6 years.With longer follow up, a treatment benefit of P is also seen in the hormone receptor (HR) positive cohort: IDFS hazard ratio for HR positive is 0.73 (95% CI 0.59 -0.92). IDFS hazard ratio for HR negative is 0.83 (95% CI 0.63 -1.10). No new cardiac safety concerns emerged. One additional primary cardiac event (heart failure) was reported in the P arm and 1 additional patient in each arm had a secondary cardiac event resulting to 18 and 8 for primary cardiac events and 65 and 68 for secondary cardiac events in the P and placebo arms, respectively. The benefit of P in HER2+ early BC is maintained, with the greatest benefit continuing to be observed in the node positive population. With longer follow-up, the benefit of P no longer appears to depend on HR status. Continued follow up of patients is very important to determine possible benefit for OS. A calendar-driven third interim OS analysis is planned in 2.5 years, and the event-driven final OS analysis is planned when 640 deaths have occurred. Citation Format: Martine Piccart, Marion Procter, Debora Fumagalli, Evandro de Azambuja, Emma Clark, Michael S. Ewer, Eleonora Restuccia, Guy Jerusalem, Susan Dent, Linda Reaby, Hervé Bonnefoi, Ian Krop, Tsang-Wu Liu, Tadeusz Pieńkowski, Masakazu Toi, Nicolas Wilcken, Michael Andersson, Young-Hyuck Im, Ling-Ming Tseng, Hans-Joachim Lueck, Marco Colleoni, Estefania Monturus, Mihaela Sicoe, Sébastien Guillaume, José Bines, Richard Gelber, Giuseppe Viale, Christoph Thomssen. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [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 GS1-04.

Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [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 PD5-11.

Background: Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T) and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, and does so more effectively than T in vitro. Based on ex vivo experiments with cells collected from patients (pts) before and after treatment, M induces adaptive immunity, including enhanced T-cell clonality and induction of HER2-specific T- and B-cell responses. The SOPHIA trial (NCT02492711) showed that in pts with pretreated HER2+ metastatic breast cancer (MBC), M+chemotherapy improved progression-free survival vs T+chemotherapy, with comparable safety. M is intended to be dosed at 15 mg/kg every 3 weeks, with infusions over 120 min at every cycle (C). A substudy of SOPHIA was conducted to evaluate the safety and tolerability of reduced infusion times from C2 onward. Methods: Eligible pts had HER2+ MBC after ≥4 lines of prior therapy for MBC, including prior T, pertuzumab, and ado-T emtansine. Enrolled pts received a 120-min M infusion, with or without chemotherapy, in C1, then either 60- or 30-min infusions in C2 and beyond. This single-arm substudy was unblinded, with no comparator. The primary objective was incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of C2. Incidence of all IRRs was a secondary objective. Results: Of 88 pts enrolled, 69 received M+chemotherapy and 19 received M alone. Mean age was 54.5 years; 99% were female and 71% white. The median number of cycles of M received was 3 (range 1-17). Overall, 7 pts were assigned to received 60-min M infusions starting at C2 (range 1-17 cycles), and 76 pts were assigned to received 30-min M infusions starting at C2 (range 1-14 cycles). Five pts did not receive C2 treatment due to non-radiologic progressive disease, unrelated adverse event (AE), patient or physician decision, or loss to follow-up. Eighty (91%) pts had premedication for IRRs. No pt had Grade ≥3 IRR. Overall, 18 (21%) had IRRs (2 Grade 1, 16 Grade 2), all but 1 of which occurred in C1 (120 min). Of the 18 pts with IRRs, 17 (94%) were premedicated and 10 (56%) were treated for IRRs. The overall rate of IRRs in premedicated pts was 21% (17/80) and in non-premedicated pts was 13% (1/8). One pt experienced IRRs in both C1 and C2 (Grade 2 in C1 and Grade 1 in C2); the same patient then received 6 additional cycles of M (30 min) with no IRRs after C2 (C3-8) and had no premedication after C1. No pt discontinued treatment due to an IRR. Of 88 pts enrolled, 85 (97%) pts experienced an AE, and 7 (8%) had Grade ≥3 AEs. Fifty (57%) pts had M-related AEs. The most common (>5% of pts) M-related AEs were IRRs in 17 (19%), fatigue in 9 (10%), diarrhea in 5 (6%), and aspartate aminotransferase increase in 5 (6%). Serious AEs occurred in 13/88 pts (15%), none of which were considered M-related by the investigator. Conclusions: In this heavily pretreated population, shorter M infusion times did not lead to an increase in IRRs. IRRs were most likely to occur during C1 when the infusion time was 120 min. No Grade ≥3 IRRs were observed. Of 18 pts with Grade 1-2 IRRs, only 1 had an IRR after C1. These results showed that the acceptable safety and tolerability profile of M was maintained even after infusion time is reduced to 30-min from C2 onward. Shorter infusion times may reduce the burden of chronic M therapy on pts, caregivers, and clinic staff. Citation Format: William J. Gradishar, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Rosanna Berardi, Michelino De Laurentiis, Shakeela W. Bahadur, Young-Hyuck Im, Cynthia Lynch, Yelena Novik, Sutton Edlich, Edwin Rock, Shengyan Hong, Hope S. Rugo, SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results [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 P1-18-04.

Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). Little is known about the potential contribution of tumor alterations in non-DDR genes to modulating sensitivity to PARP inhibitors in the clinic. In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was tested by FoundationOne®. To support exploratory identification of tumor gene alterations associated with best vs worst outcomes, pts were mapped into 2 groups: [1] BEST: Pts in TALA arm with OS ≥ 30 mo and duration of treatment ≥ 24 mo, Pts in CT arm with OS ≥ 30 mo; [2] WORST: Pts in TALA or CT arm with a PFS event (PD by Independent Radiological Facility or death) ≤ 12 wks. 2 pts had short PFS but long OS and were initially mapped to both groups but then assigned to BEST and excluded from WORST. Results: Exploratory heat map visualizations of known/likely pathogenic genetic alterations defined by the FoundationOne® gene panel were used to assess differences in genetic alterations between BEST and WORST in TNBC and non-TNBC subpopulations, leading to the identification of MYC and RAD21 as commonly altered genes of high interest. Based on these results showing imbalances in tumor amplification events between BEST and WORST outcome pts, Cox regression analysis was used to explore potential associations of MYC or RAD21 amplification with OS across the evaluable ITT population. In TNBC pts receiving TALA, OS was shorter with MYC amplification than without [HR (95% CI) 1.877 (1.102, 3.196)]. No such association was evident in TNBC pts receiving CT [HR (95% CI) 0.706 (0.303, 1.643)]. In contrast, for non-TNBC pts receiving TALA, no association with OS was evident for MYC amplification versus without [HR (95% CI) 0.603 (0.310, 1.173)], while for pts receiving CT OS was shorter with MYC amplification than without [HR (95% CI) 1.917 (1.037, 3.544)]. RAD21 amplification status was not associated with OS in either TNBC or non-TNBC patients for either treatment arm, although it should be noted that two RAD21 subgroups were very small (n=7 and 11; others had n ≥ 21). Conclusions: Based on these exploratory, retrospective analyses MYC amplification was associated with shorter OS in TNBC pts receiving TALA. This may reflect the role of MYC in positive regulation of genes involved in homologous recombination such as RAD51 (Carey et al, Cancer Res 2018;78(3):742-757). MYC and RAD21 are both located at 8q24 and frequently coamplified in breast cancer (eg, Annunziato et al, Nat Commun. 2019;10(1):397), hence the lack of association of RAD21 amplification with outcome in TNBC suggests that the association of MYC amplification with shorter OS seen in pts receiving TALA may be gene-specific. Further investigation is warranted. Funding: Pfizer TNBCNon-TNBCTALACTTALACTGene AlterationBest n=10Worst n=15Best n=7Worst n=16Best n=17Worst n=11Best n=20Worst n=11MYC amplification0 (0%)7 (47%)2 (29%)6 (38%)5 (29%)1 (9%)3 (15%)5 (46%)RAD21 amplification1 (10%)2 (13%)3 (43%)5 (31%)5 (29%)1 (9%)7 (35%)4 (36%) Citation Format: Johannes Ettl, A. Douglas Laird, Joanne L. Blum, Hope S. Rugo, Sara A. Hurvitz, Miguel Martín, Henri Roché, Young-Hyuck Im, Annabel Goodwin, Rinat Yerushalmi, Tiziana Usari, Silvana Lanzalone, Akos Czibere, Julia Hopkins, Lee A. Albacker, Lida A. Mina, Jennifer K. Litton. A retrospective analysis of association of MYC and RAD21 amplification with final overall survival (OS) data in the phase 3 EMBRACA study with talazoparib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-07.

Background: MONALEESA-7 (NCT02278120), the first large randomized phase III clinical trial dedicated to investigating a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus ET vs ET + placebo (PBO) in pre- or perimenopausal patients with HR+/HER2− ABC, previously demonstrated a statistically significant improvement in OS with the addition of ribociclib (RIB) to ET vs PBO + ET (median, not reached vs 40.9 months; HR, 0.71 [95% CI, 0.54-0.95]; P = .00973; Im SA, et al. N Engl J Med. 2019). This concluded the protocol-defined final analysis of OS and the patients and investigators were unblinded to their treatment assignment allowing patients on the PBO arm to cross-over to RIB treatment. Longer follow-up allows for more events to further characterize the long-term survival benefits. Here we report an exploratory update of OS after a minimum of ~ four years of follow-up, an additional 20 months since the last report. Methods: Pre- or perimenopausal patients with HR+/HER2− ABC were randomized 1:1 to receive RIB or PBO plus goserelin with either a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) or tamoxifen. RIB is approved in combination with an NSAI in pre- or perimenopausal patients. Patients who had received a prior CDK4/6i or ET in the advanced setting were excluded. Patients who received ET in the (neo)adjuvant setting or ≤ 1 prior line of chemotherapy for advanced disease were eligible to enroll. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Additional post-progression endpoints such as progression-free survival 2 (PFS2), time to chemotherapy (CT) and CT-free survival were also evaluated and summarized. Results: The data cutoff for this updated OS analysis was 29 June 2020, and the median follow-up was 53.5 mo (min, 46.9 mo). These updated results with extended follow-up demonstrated an OS benefit with RIB + ET vs PBO + ET (median, 58.7 vs 48.0 mo; HR, 0.76 [95% CI, 0.61-0.96]). In patients receiving an NSAI, a similar OS benefit was observed with RIB + NSAI vs PBO + NSAI (median, 58.7 vs 47.7 mo; HR, 0.80 [95% CI, 0.62-1.04]). The survival benefit shown in subgroup analyses was consistent with the intent-to-treat (ITT) population. PFS2, time to chemotherapy (CT), and CT-free survival for the ITT and NSAI populations are in the Table. Among the patients who discontinued study treatment, 77.3% and 78.1% in the RIB + ET vs PBO + ET arms received a subsequent antineoplastic therapy, respectively, and 12.9% and 26.1% received a subsequent line of CDK4/6i. Additionally there were 15 patients in the PBO arm that crossed over to the RIB arm following unblinding and prior to disease progression. Conclusions: With an extended follow-up of more than 4 years, RIB + ET continued to demonstrate a clinically relevant OS benefit compared with ET alone in pre- or perimenopausal patients with a median OS ~5 years with RIB +ET in HR+/HER2− ABC. A similar benefit with RIB was observed for PFS2, time to CT, and CT-free survival. ITTNSAI cohortRIB + ETn=335PBO + ETn=337RIB + NSAIn=248PBO + NSAIn=247PFS2Events, n (%)177 (52.8)221 (65.6)131 (52.8)159 (64.4)Median, mo44.231.043.630.4HR (95% CI)0.68 (0.56-0.83)0.69 (0.55-0.87)Time to first CTEvents, n (%)144 (43.0)173 (51.3)107 (43.1)129 (52.2)Median, mo50.936.850.936.0ITT HR(95% CI)0.69 (0.56-0.87)0.66 (0.51-0.85)CT-free survivalEvents, n (%)190 (56.7)236 (70.0)139 (56.0)169 (68.4)Median, mo42.426.442.525.9HR (95% CI)0.67 (0.55-0.81)0.64 (0.51-0.81) Citation Format: Debu Tripathy, Seock-Ah Im, Marco Colleoni, Fabio Franke, Aditya Bardia, Nadia Harbeck, Sara Hurvitz, Louis Chow, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Rafael Villanueva Vazquez, Kyung Hae Jung, K Govind Babu, Paul Wheatley-Price, Michelino De Laurentiis, Young-Hyuck Im, Sherko Kümmel, Nagi El-Saghir, Mei-Ching Liu, Sharonjeet Kaur, Claudia Gasch, Craig Wang, Yongyu Wang, Arunava Chakravartty, Yen-Shen Lu. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-04.

Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.

Background: TALA significantly prolonged progression-free survival vs physician's choice of chemotherapy (PCT) (hazard ratio [HR] 0.54 [95% CI 0.41-0.71]; P < 0.001) and improved patient-reported outcomes (PRO) in patients (pts) with HER2- ABC (locally advanced/metastatic) with a gBRCA1/2 mutation. We report results of the final OS analysis (secondary endpoint). Methods: Pts randomized 2:1 to TALA or PCT. OS HR was based on stratified Cox regression model (treatment as covariate); P value on stratified log-rank test. Results: 431 pts were randomized (287 TALA/144 PCT), 412 treated (286 TALA/126 PCT). By Sept 30, 2019, 216 deaths (75.3%) occurred for TALA and 108 deaths (75.0%) PCT; median follow-up 44.9 and 36.8 months, respectively. HR for OS was 0.85 (95% CI 0.67-1.07; P = 0.17); survival probability was higher for pts receiving TALA at 24, 36, and 48 months (Table 1). OS results were consistent across subgroups, eg by prior platinum or hormone receptor status. Most pts received post-study therapies; 32.6% of pts in the PCT arm received a PARP inhibitor post-study (4.5% for TALA arm). Grade 3-4 AEs occurred in 69.6% (TALA) and 64.3% (PCT) pts; AEs leading to permanent treatment discontinuation (excluding progressive disease) occurred in 5.9% and 8.7% of pts. Extended follow-up showed statistically significant overall improvements and delays in time to definitive clinically meaningful deterioration in both global health status/QoL and breast symptoms scales favoring TALA vs PCT (P < 0.01 for all), consistent with initial PRO analyses. Table 1.OS and post-study therapy (intent-to-treat)Talazopariboral 1 mg QDN = 287PCTaN = 144Deaths (%)216 (75.3)108 (75.0)HR (95% CI)0.85 (0.67-1.07); P = 0.17Median, mo. (95% CI)b19.3 (16.6-22.5)19.5 (17.4-22.4)Survival probability (95% CI) at Monthc120.71 (0.66-0.76)0.74 (0.66-0.81)240.42 (0.36-0.47)0.38 (0.30-0.47)360.27 (0.22-0.33)0.21 (0.14-0.29)480.19 (0.14-0.25)0.07 (0.02-0.15)Post-study antineoplastic therapy, n (%)233 (81.2)110 (76.4)PARP inhibitor, n (%)13 (4.5)47 (32.6)Platinum-based therapy, n (%)133 (46.3)60 (41.7)CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; mo., months; OS, overall survival; PARP, poly(ADP-ribose) polymerase; QD, once daily.aPCT, physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine).bDuration of OS based on KM estimates.cProbability estimated from the KM curve and CI calculated with product-limit method. Conclusions: In gBRCA1/2-mutated HER2- ABC, TALA did not significantly improve OS over PCT (HR 0.85; 95% CI 0.67-1.07; P = 0.17); analysis not adjusted for subsequent therapies. TALA was generally well-tolerated with no new safety signals. PRO continued to favor TALA. Funding: Pfizer (Medivation) Citation Format: Jennifer K. Litton, Sara A. Hurvitz, Lida A. Mina, Hope S. Rugo, Kyung-Hun Lee, Anthony Gonçalves, Sami Diab, Natasha Woodward, Annabel Goodwin, Rinat Yerushalmi, Henri Roché, Young-Hyuck Im, Wolfgang Eiermann, Ruben G. Quek, Tiziana Usari, Silvana Lanzalone, Akos Czibere, Joanne L. Blum, Miguel Martin, Johannes Ettl. Talazoparib (TALA) in germline BRCA1/2 (gBRCA1/2)-mutated human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): Final overall survival (OS) results from randomized Phase 3 EMBRACA trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT071.

BACKGROUND: Women with triple-negative breast cancers (TNBCs) represent a significant treatment challenge as they have a relatively poor prognosis and no effective targeted therapy exists. Although TNBCs are often discussed as a single disease entity of breast cancers, in fact they are very heterogeneous. The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate TNBCs among patients, who received adjuvant chemotherapy after curative surgery, into those with high or low risk for distant recurrence. METHODS: We tested whether the results of a NanoString expression assay that targeted 245 prospectively selected genes and used mRNA extracted from paraffin wax-embedded tumor tissues would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high). RESULTS: NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63, and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis in this patients’ cohort and were validated with cross-validation. The proportions of patients categorized as having low or high risk were 75% and 25%, respectively. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low- and high-risk groups according to gene expression signature were 62% (95% CI, 48.6–78.9%) and 85% (95% confidence interval, CI, 79.2–90.7%), respectively. When adjusting for tumor–node–metastasis (TNM) stage, the distant recurrence-free survival (DRFS)s in the low-risk groups were significantly longer than that in the high-risk group (p CONCLUSION: A seven-gene signature could be used as a prognostic model to predict DRFS in patients with TNBC who received curative surgery followed by adjuvant chemotherapy. Citation Format: Yeon Hee Park, Hae Hyun Jung, In-Gu Do, Eun Yoon Cho, Insuk Sohn, Sin-Ho Jung, Won Ho Kil, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn, Young-Hyuck Im. A seven-gene signature can predict distant recurrence in patients with triple-negative breast cancers (TNBCs) who receive adjuvant chemotherapy following curative surgery of the primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-20.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been used widely in patients with locally advanced breast cancer (LABC). NAC has the added advantage of increasing breast conservation rates with similar disease-free and overall survival compared with adjuvant chemotherapy. A subset of patients receiving NAC experiences early failure during the course of therapy or within a short period after breast surgery. There are no established predictors for early therapy failure in LABC patients who received NAC. This study was performed to identify candidate actionable mutation to explain early failure and refractoriness to chemotherapy in BC patient groups that may not benefit from NAC. METHODS: Seventy eight patients among 397 Patients with LABC (cT2-4N0-3) who were available for preoperative FFPE tumor block for next generation sequencing (NGS) included in this analysis excluding 21 patients whose FFPE were not qualified for Ampliseq. Early failure was defined as the development of an inoperable state caused by locoregional or systemic progression during NAC or relapse after curative surgery within 1 year after the initiation of NAC. Patients who developed recurrence after 1 year from the start of NAC or exhibited no failure during the follow-up period were defined as control in this study. Thus, our cohort was composed of pCR (pathologic CR to NAC), early failure, and control. The clinicopathological characteristics and disease courses of the patients whose disease progressed within 1 year of receiving neoadjuvant chemotherapy were analyzed to compare with the other patients. Using the Ion Torrent Ampliseq Cancer Panel v2 after DNA isolation from FFPE samples, we sequenced 2,855 loci from 50 cancer-related genes to identify genetic mutations in 78 BC patients who received NAC for patients with locally advanced BCs and available preoperative tumor tissue. RESULTS: Thirty-eight of the 397 patients (9.6%) exhibited progression within 1 year after receiving neoadjuvant chemotherapy. Among 78 patients who were available tumor tissue in this analysis, the number of patients with early failure, pCR, and control was 22, 19, and 27, respectively. The sequencing analysis revealed TP53 mutations were observed in 95% or more patients, evenly irrespective of patients’ group. Missense mutations in ALK and BRAF were found to be predominantly much higher in patients with early failure than in other groups (p CONCLUSION: ALK and BRAF genes are associated with early failure in this analysis. Our results support that targeted sequencing using cancer panel may function to identify actionable targets which are associated with responsiveness to NAC for patients with LABC. Further research to figure out the functioning role of these genes for each group is warranted. Citation Format: Yeon Hee Park, Moon Ki Choi, In-Gu Do, Eun Yoon Choi, Won Ho Kil, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn, Young-Hyuck Im. ALK and BRAF genes are associated with early failure of breast cancer (BC) who received primary neoadjuvant chemotherapy for patients with locally advanced BCs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-44.

Background: Afatinib is an oral, irreversible ErbB family blocker with anti-tumour activity in patients (pts) with HER2-positive metastatic breast cancer (MBC) after failure on trastuzumab.1 Preclinically, afatinib + vinorelbine (AV) showed an additive effect; clinically, the AV combination had a manageable safety profile and showed activity in two Phase I trials.2,3 This randomized, open-label, Phase III trial (LUX-Breast 1) compared AV with trastuzumab + vinorelbine (TV) in pts with HER2-positive MBC who had progressed on a prior T-based regimen. Methods: Pts with HER2-positive MBC and failure of one T-based regimen (adjuvant/first-line) were randomized 2:1 to AV (40 mg/day oral + 25 mg/m2/week iv) or TV (2 mg/kg/week iv after 4 mg/kg loading dose + 25 mg/m2/week iv). Treatment continued until progressive disease (PD) or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) by investigator review; secondary endpoints included objective response rate (ORR), overall survival (OS) and safety. Planned accrual was 780 pts. Results Between August 2010 and April 2013, 508 patients were randomized (AV:339, TV:169). Baseline characteristics were balanced in both arms (mean age 52 yrs, Asian 50.6%, White 41.6%, ER/PR positive 28.7%). 41.1% of pts failed on prior adjuvant and 58.9% on 1st line T-based treatment. A pre-planned risk/benefit assessment was found unfavorable by the DMC and recruitment was stopped. Pts ongoing on AV therapy were switched to TV, received A or V monotherapy, or stopped treatment. Primary endpoint analysis was performed with 307 of the originally 484 planned PFS events (211 [62.2%] AV arm; 96 [56.8%] TV arm). Median PFS was 5.5 months with AV vs 5.6 months with TV (HR 1.10; 95% CI 0.86, 1.41; P=0.4272). ORR was 46.1% with AV and 47.0% with TV (OR 1.04; 95% CI 0.71, 1.51; P=0.8510). OS analysis was based on 144 (28.4%) OS events (108 [31.9%] in AV arm; 36 [21.3%] in TV arm). Median OS was 19.6 months with AV and 28.6 months with TV (HR 1.76; 95% CI 1.20, 2.59; P=0.0036). The most common drug-related AEs were diarrhea (80.1%), neutropenia (75.1%) and rash (45.1%) with AV, and neutropenia (78.7%), leukopenia (37.3%) and anemia (27.8%) with TV. Rate of infections (53.0% vs 40.5%) was higher with AV vs TV. More AV than TV pts discontinued due to AEs (15.4% vs 7.1%). Fatal AEs were reported for 18 (5.3%) in the AV vs 5 (3.0%) pts in the TV arm, and were mainly associated with PD (9 pts in AV and 1 in TV arm). Three AV pts died due to treatment-related causes (sepsis/multi-organ failure; septic shock; pulmonary fibrosis). Conclusions: AV and TV demonstrated similar PFS and ORR, but OS diverged and was shorter for AV compared to TV in pts with HER2-positive MBC. The safety profile of AV was consistent with the individual monotherapies, but its tolerability compared unfavorably to TV. Analyses are ongoing to elucidate potential factors (e.g. impact of follow up treatments) contributing to the diverging PFS and OS outcomes. 1. Lin NU et al. Breast Cancer Res Treat 2012;133:1057-65 2. Bahleda R et al. J Clin Oncol 2011;29; abs 2585 3. Masuda N et al. SABCS 2013 abs P4-16-11. Citation Format: Nadia Harbeck, Chiun-Sheng Huang, Sara Hurvitz, Dah-Cherng Yeh, Zhimin Shao, Seock-Ah Im, Kyung Hae Jung, Kunwei Shen, Jungsil Ro, Jacek Jassem, Qingyuan Zhang, Young-Hyuck Im, Marek Wojtukiewicz, Qiang Sun, Shin-Cheh Chen, Rainer-Georg Goeldner, Annick Lahogue, Martina Uttenreuther-Fischer, Binghe Xu, Martine Piccart-Gebhart, on Behalf of the LUX-Breast 1 Study Group. Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-01.

Purpose: Although both gBRCA1/2 mutations are known to increases incidences of breast and ovarian cancer by abruption in homologous recombination pathway, gBRCA1 mutant mainly present with a molecular subtype of triple negative breast cancer (TNBC) and gBRCA2 with hormone receptor (HR) positive which we have little understanding regarding the underlying pathophysiology. In this study, we have comprehensively analyzed clinical characteristics and somatic mutation in gBRCA1/2 mutant patients. Methods: Patients with gBRCA mutation tested (n=2720) in Samsung Medical Center between Jan 2007 to Oct 2018 were retrospectively reviewed. 386 patients were identified as gBRCA mutant and follow-up period less than 2 years (n=105), insufficient clinical data (n=22) and no surgical treatment (n=6) were excluded. Total of 259 patients, gBRCA1 (n=128), gBRCA2 (n=126) and both gBRCA1/2 mutation (n=5), were analyzed. Among the study population, 46 patients had deep target sequencing data with 40 patients also available for matched transcriptome outcome. Results: Median age was 40 years old (range 23-68). Patients were mostly under pre-menopausal status (81.2%) with invasive ductal carcinoma pathology (86.2%). Initial stage at diagnosis were stage 0 (4.7%), 1 (30.3%), 2 (40.6%) and 3 (24.4%). A novel mutation was observed in 16.9% of the study population and frameshift (44.9%) and nonsense (31.5%) mutations were predominant. Molecular subtypes were as follows: HR-positive (n=125, 49.2%), HR/HER2 positive (n=10, 3.9%), HER2 positive (n=3, 1.2%) and TNBC (n=116, 46.7%). TNBC was observed mostly in gBRCA1 mutant patients (71.9% vs. 19.1%) and HR-positive in gBRCA2 mutant patients (76.2% vs. 22.7%). Sixty-seven patients (26.4%) experienced disease recurrence and median time to recurrence were 145.0 months (95% confidential interval 107.3-170.2). Looking into co-altered somatic mutation using target sequencing (n=45), notably, alteration in other DNA-damage response pathway-related genes, such as TP53 (60%), ATR (27%), CHEK2 (20%), MSH6 (20%), were identified. Evaluated for mutual exclusivity, only gBRCA2 was significantly (P Conclusions: From our dataset, we have witnessed similar clinical characteristics but the difference in molecular subtype between gBRCA1/2 mutant. Despite the fact that both gBRCA1/2 mutations disrupt the homologous recombination pathways, this study provides early evidence regarding the hypothesis that difference in co-occurred somatic alteration between gBRCA1/2 lead to different carcinogenesis mechanism which consequences different molecular subtype. Detail analyses using paired transcriptome result will be presented in the poster. Citation Format: Sehhoon Park, Eunjin Lee, Seri Park, Sohee Lee, Joon Young Hur, Sang Eun Yoon, Kangkook Lee, Jang Ho Cho, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Woong-Yang Park, Yeon Hee Park. Clinical characteristics and combined somatic mutation using target sequencing among breast cancer patients with germline BRCA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3502.

Background: The ratio of involved to retrieved lymph nodes (LNR) is suggested as a prognostic factor in operable breast cancer. However, there are conflicting results regarding its clinical significance after neoadjuvant chemotherapy. We investigated the prognostic value of LNR with a thorough evaluation of potential prognostic factors in a large cohort constructed from Health Insurance Review and Assessment Service database of Korea. Patients and method: This retrospective analysis is based on the data of 814 patients with clinical stage II/III breast cancer treated with four cycles of adriamycin/cyclophosphamide (AC) followed by four cycles of docetaxel (DOC) before surgery. We evaluated the clinical significance of the LNR (3 categories: Low, 0-0.20 vs. Intermediate, 0.21-0.65 vs. High, 0.66 -1.00) using Kaplan-Meier method, log-rank test, and Cox proportional hazard regression model. Result: A total of 799 patients underwent breast surgery (Median age 45, range 16-74; Mastectomy 369, Lumpectomy 380, and Others 50). Axillary lymph node dissection was performed in 704 (88.1%) patients. Pathologic complete response (pCR, pT0/isN0) was achieved in 129 (16.1%) of 799 patients (HR+/HER2-, 34/373 [9.1%]; HER2+, 45/210 [21.4%]; TNBC 50/216 [23.1%]). The mean numbers of involved LN and retrieved LN were 2.70 (range 0-42) and 13.98 (range 1-64), respectively. The mean LNR was 0.17 (Low, 574 [71.8%]; Intermediate, 170 [21.3%]; High, 55 [6.9%]). In univariate analysis, LNR was significantly associated with worse relapse-free survival (3-yr RFS rate 84.8% in low vs. 66.2% in intermediate vs. 54.3% in high; P Multivariate analysis for relapse-free survival P-valueHR95%CIAGE ( Conclusion: LNR is not superior to ypN-stage in predicting clinical outcome of breast cancer after neoadjuvant chemotherapy. Citation Format: Se Hyun Kim, Jee Hyun Kim, Tae-Yong Kim, In Sil Choi, Yee Soo Chae, Sun Kyung Baek, Seok Yun Kang, In Hae Park, Yoon Ji Choi, Soohyeon Lee, Joo Hyuk Sohn, Yeon-Hee Park, Young-Hyuck Im, Jin-Hee Ahn, Sung-Bae Kim, Kyung Hae Jung. Prognostic value of axillary nodal ratio after neoadjuvant chemotherapy of AC followed by docetaxel: A multicenter retrospective cohort study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-33.

Background and Purpose Studies have suggested that the antigenicity of tumor cell is highly correlated with response to immune checkpoint inhibitors. Checkpoint blockade has been found to be particularly effective in tumors with high tumor mutational burden (TMB) in certain indications such as melanoma and NSCLC, while cancers with lower TMB have been shown to be less responsive to checkpoint inhibitors. In HER2-positive metastatic breast cancer (MBC), TMB has potential to be a candidate prognostic or predictive marker for conventional treatments including HER2 targeting agents. This research was conducted to explore the clinical implication of somatic TMB in a well-defined HER2-positive MBC population who were previously treated but progressed. Methods Forty-six patients with HER2-positive MBC who have progressed from more than two HER2-directed therapies were enrolled from 2007 to 2016. Whole exome sequencing was performed on FFPE tumor samples and matched normal tissue. Sequencing reads were aligned to reference human genome using BWA-MEM followed by standard pre-processing steps and GATK to generate analysis ready BAM files. MuTect suite was used to generate somatic single nucleotide variants (SNV) calls using default parameters by comparing BAM files from tumor and matched normal samples. TMB for a subject was defined as the sum of somatic non-synonymous SNVs that passed all the filters described. Results Among 46 patients, 13 (28.3%) patients were determined to estrogen receptor (ER)-positive and 9 (19.6%) patients were determined to progesterone receptor (PR)-positive in immunohistochemistry (IHC) analysis. The median age 48 years (range: 29-68) and all (100%) patients were female. 20 patients (43.5%) were recurrent MBC compared to de novo (n = 26, 56.5%). 16 (34.6%) patients demonstrated more than 100 mutations (and defined as high TMB in this population). The median follow up of duration was 57.5 months (95% CI: 55.4 - 60.6). The median overall survival (OS) according to low or high TMB status (44.9 months vs. 85.8 months) was significantly different (p = 0.016). In a multivariate Cox regression analysis, TMB was the only independent prognostic factor for good OS when adjusted for age and recurrence (Hazard ratio = 0.32, 95% CI, 0.103 - 0.998, p = 0.049). Conclusions Data implicated that high TMB can be a prognostic marker that predicts good OS outcomes with conventional HER2-directed treatments and chemotherapy. Furthermore, future trials using TMB as a stratification marker could identify the right population with potential to respond to immune checkpoint inhibitor after recurrence following HER2-directed treatments. To our knowledge this is the first report that tumor mutation burden (TMB) associate with response to standard of care therapy in HER2+ breast tumors. Citation Format: Yeon Hee Park, Kyunghee Park, Song Ee Park, Eunjin Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Hun Jung, Chooghoon Lee, Woong-Yang Park, Razvan Cristescu. Clinical implication of mutation load in patients with HER2-positive refractory metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2602.

Breast cancers (BC) in younger, premenopausal patients (YBC) tend to be more aggressive with worse prognosis, higher chance of relapse and poorer response to endocrine therapies compared to breast cancers in older patients. The proportion of YBC (age ≤ 40) among BC in East Asia is estimated to be 16-32%, significantly higher than the 7% reported in Western countries. In addition, approximately half of the Asian BC patients were premenopausal compared to 15-30% in the West. To characterize the molecular bases of Asian YBC, we have performed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) on tumor and matched normal samples from 168 Korean BC patients consisting of 106 YBC cases (age ≤ 40) and 62 OBC cases (age > 40). We then performed comparison analyses with the TCGA BC cohort consisting of 1,116 tumors from primarily Caucasian patients, also grouped by age into YBC (age ≤ 40), IBC (40 < age ≤ 60) and OBC (age > 60). We performed logistic regression analyses to identify differentially expressed (DE) genes and pathways among age-based cohorts while controlling for the confounding effects of molecular subtype, tumor purity and stage. Within the Asian cohort, we found that estrogen response, endocrine therapy resistance, and various metabolism pathways are up-regulated in YBCs while cell cycle, proliferation and inflammatory pathways are up-regulated in OBCs. To separately examine molecular signatures from tumor, stroma and normal compartments, we used non-negative matrix factorization (NMF) analyses to virtually dissect bulk tumor expression data and identified 14 factors including 3 factors associated with normal tissues, 1 factor associated with stroma and 1 factor associated with tumor infiltrating leukocytes (TILs). By examining the correlation between pathway gene expression and NMF factors, we inferred that DE pathways such as fatty acid metabolism, bile acid biosynthesis, and epithelial-to-mesenchymal transition (EMT) were mainly active in stromal and normal tissue compartments. The TIL factor was significantly enriched in Asian BCs relative to Caucasian BCs with the highest TIL factor weight observed in Asian OBCs. Using gene expression signatures representing distinct types of TILs, we classified the combined cohort into three subtypes of varying TIL activities. Consistent with results from the NMF analysis, the TIL-high subtype is also significantly enriched in Asian BCs relative to Caucasian BCs. To our knowledge, this is the first large-scale multi-omics study of Asian breast cancer. Comparative analyses of multi-omics profiles from Asian and primarily Caucasian BC cohorts identified distinguishing molecular signatures associated with Asian BCs. Further, many signatures appeared to be specific to non-tumor compartments within bulk tumor, indicating that young Asian BCs may harbor distinctive tumor microenvironment. Citation Format: Yeon Hee Park, Ying Ding, Soo-Hyeon Lee, Hae Hyun Jung, Woosung Chung, Soonweng Cho, Jin-Ho Kim, Shibing Deng, Yoon-la Choi, Julio Fernandez, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Seok Jin Nam, Woong-Yang Park, Zhengyan Kan. Comparative analyses of multi-omics profiles reveal distinctive molecular signatures of young Asian breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3370. doi:10.1158/1538-7445.AM2017-3370

Background We investigated the association between gene-expression (GEP) based markers and distant event free survival (DEFS) in HER2+ breast cancer patients (pts) in the NeoSphere study. Methods In NeoSphere HER2+ pts were randomized to neoadjuvant HD, PHD, PH or PD (H = trastuzumab, P = pertuzumab, D = docetaxel). Affymetrix-based GEPs were generated in 367/417 pts (88%). We evaluated the association with DEFS of 10 biomarkers in all patients with arms pooled and by each arm, and separately by ER status: six immune-related metagenes (CD8, IGG and MHC2, related to T cells, plasma cells and antigen presenting cells, respectively; MHC1, STAT1 and IF.I related to HLA cass I genes, and to genes modulated by interferons), ESR1 and an ER-related score (ERS), a proliferation marker (MKS) and ERBB2 expression. We re-assessed findings in GEPs derived from ER-/HER2+ pts of the NOAH trial treated with neoadjuvant chemotherapy (CT) or CT and trastuzumab (CTH). Results Median follow-up was 5 years. Overall none of the markers was significant, but an interaction test for biomarkers and ER status was significant for MHC1, MHC2, STAT1, and marginally for MKS. In ER+/HER2+ tumors, immune markers were not significant, but higher proliferation (MKS; HR 2.12 [1.07-4.19], p = 0.03) was linked to higher risk, with a similar trend for low ERS (p = 0.097). In ER-/HER2+ tumors higher MHC2 (HR 0.53 [0.36-0.79]; p = 0.002), MHC1 (HR 0.41 [0.22-0.77], p = 0.005) and STAT1 (HR 0.69 [0.49-0.97], p = 0.036) were linked to better DEFS. Outcome for high MHC1 tertile was excellent and similar in all treatment arms. Low/int MHC1 pts treated with PHD had a trend for better DEFS compared to other treatments (HR 0.41 (0.14-1.21), p = 0.11). In cases reaching pCR higher MHC1 (p = 0.009), MHC2 (p = 0.006), IGG (p = 0.027) and STAT1 (p = 0.008) were linked to better DEFS. For instance, the 5 yrs DEFS for high and low MHC1 tertiles was 100% and 74.6%, respectively. Similarly, in ER-/HER2+ pts from NOAH, the 5-yrs DEFS in high, int and low MHC1 tertiles was 88.1%, 68.4% and 48.1%, respectively (p = 0.015). Prognosis was similar and good in patients with high MHC1 receiving CT or CTH (p = 0.674). Instead, in low/int MHC1 groups, CTH compared to CT significantly improved DEFS (HR 0.39 [0.16-0.93], p = 0.035). Also in NOAH, the 5 yrs DEFS of pCR cases was influenced by baseline MCH1 (100% and 76.2% with high and low/int MHC1, respectively). Conclusions In this exploratory analysis of NeoSphere, different biological functions were linked to DEFS in ER+ (proliferation and ER-related genes) and ER- (immune related) cases. In particular outcome of ER-/HER2+ with high MHC1 was good. However, in this group the benefit from adding trastuzumab to CT or pertuzumab in the PHD regimen was relatively small. Instead, the benefit seemed significant and large in cases of low/int MHC1, who had higher relapse risk. Of note, baseline immune markers of ER-/HER2+ tumors were linked to different DEFS also for cases achieving pCR. Citation Format: Giampaolo Bianchini, Tadeusz Pienkowski, Young-Hyuck Im, Giulia Valeria Bianchi, Ling-Ming Tseng, Mei-Ching Liu, Ana Lluch, Vladimir Semiglazov, Juan de la Haba-Rodríguez, Do-Youn Oh, Brigitte Poirier, Jose Luiz Pedrini, Pinuccia Valagussa, Luca Gianni. Baseline molecular markers and risk of distant relapse in the NeoSphere study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3940.

Breast cancers (BC) in younger, premenopausal patients (YBC) tend to be more aggressive with worse prognosis, higher chance of relapse and poorer response to endocrine therapies compared to breast cancers in older patients (OBC). The proportion of YBC (age ? 40) among BC in East Asia is estimated to be 16-32%, significantly higher than the 7% reported in Western countries. Genomic and molecular characterizations have deepened our understanding of breast cancer biology in areas ranging from intrinsic subtypes to treatment responses, however, the molecular bases of Asian YBC remains poorly characterized. We have performed whole-exome sequencing (WES), whole-transcriptome sequencing (WTS) and high coverage targeted sequencing on tumor and matched normal samples from 133 Korean BC patients consisting of 74 YBC cases (age ? 40). We further performed immunohistochemistry (IHC) analyses to characterize tumor-infiltrating lymphocytes (TILs) in 46 tumors using four markers (CD45, CD4, CD8 and CD163). We found that BRCA1/2 germline deleterious mutations are enriched in YBC and the ER+/HER2- subtype, indicating that Asian ER+ YBC has a significant germline contribution. MutSig analysis4 identified ARID1A as a significantly mutated gene, implicating chromatin modeling as a cancer driver in Asian BC. Differential expression analyses suggested that Asian YBC differ in energy metabolism and are more active in protein synthesis than OBC tumors, whereas OBC is more proliferative than YBC. Using gene expression signatures representing distinct immune cell types and immunohistochemistry, we classified our cohort into four subtypes of varying TIL activities: high, medium, low and quiet. The majority of immunogenic cases with high TIL levels lie in ER+ or HER2+ subtypes although higher proportion is seen in TNBC. Moreover, YBC tumors appear to harbor lower levels of TIL activities than OBC, suggesting that younger patients may be less likely to benefit from immunomodulatory therapies than older patients. To our knowledge, this is the first large-scale multi-omics study of Asian breast cancer and would significantly contribute to the compendium of molecular data available for young, premenopausal breast cancer. While the major landmarks in the molecular and immune landscape of Asian BC look similar to that of the predominantly Caucasian BC cohorts, we have identified a number of distinguishing characteristics pointing to distinctive oncogenic mechanisms underlying Asian BC. Citation Format: Yeon Hee Park, Ying Ding, Soonweng Cho, Soo-Hyeon Lee, Hae Hyun Jung, Woosung Chung, Jinho Kim, Woong-Yang Park, Eric Powell, Pamela Vizcarra, Shibing Deng, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Seok Jin Nam, Zhengyan Kan. Multi-omics and immuno-oncology profiling of an Asian breast cancer cohort enriched in young and premenopausal patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-325.

Background: Poly-ADP-ribose polymerase (PARP) represents a family of enzymes of which at least two (PARP1 and PARP2) play important roles in DNA repair. PARP inhibition induces synthetic lethality in tumor cells bearing mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA 1) and breast cancer susceptibility gene 2 (BRCA 2), both of which are key components in the pathway of homologous recombination DNA repair. BMN 673 is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes (Murai et al, 2014). BMN 673 is a novel and highly potent PARP inhibitor and has shown promising single-agent anti-tumor efficacy in several tumor types in an ongoing Phase 1/2 clinical study. Methods: The purpose of this multi-center, international, open-label, 2:1 randomized Phase 3 trial (EMBRACA) is to compare the safety and efficacy of BMN 673 versus protocol-specific physician’s choice treatment (capecitabine, eribulin, gemcitabine or vinorelbine) in subjects who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. The primary objective of the study is to compare progression free survival (PFS) of subjects treated with BMN 673 as a monotherapy relative to those treated with protocol-specific physician’s choice treatment. Secondary objectives include objective response rate (ORR), overall survival (OS), safety and pharmacokinetics of BMN 673. Exploratory objectives include duration of response (DOR) and health-related quality of life assessment. Patients may be eligible if they are 18 years or older, have histologically or cytologically confirmed carcinoma of the breast, locally advanced and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy, documentation of a deleterious or pathogenic germline BRCA1 or BRCA2 mutation, ≤ 2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline in the adjuvant or metastatic setting, ECOG performance status ≤ 1, and no prior platinum treatment for metastatic disease. Patients (n=429) will be randomized 2:1 to receive either BMN 673 oral capsules once daily (1.0 mg/day) in 21-day cycles or protocol-specific physician’s choice treatment. All eligible subjects will receive study drug treatment until disease progression or unacceptable toxicity. This trial is enrolling patients from the United States, Europe, Israel, Asia/Pacific, and South America (NCT01945775). Citation Format: Jennifer K Litton, Joanne L Blum, Wolfgang Eiermann, Young-Hyuck Im, Miguel Martin, Lida Mina, Henri Roché, Hope S Rugo, Frances Visco, Charlie Zhang, Nathalie A Lokker, Debra L Lounsbury. A phase 3, open-label, randomized, parallel, 2-arm multi-center study of the oral PARP inhibitor BMN 673 versus physician's choice in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-12.