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ImportanceCancer therapy–related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD.ObjectiveTo determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy.Design, Setting, and ParticipantsA prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/− pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022.Main Outcomes and MeasuresThe outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression.ResultsOf 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046).Conclusions and RelevanceThis study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation.Trial RegistrationClinicalTrials.gov Identifier: NCT02177175

PURPOSE On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States. METHODS A retrospective analysis was conducted using electronic health record–derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria. RESULTS We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; P = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; P = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively. CONCLUSION There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.

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Supplementary Data from Increased Levels of Urinary PGE-M, a Biomarker of Inflammation, Occur in Association with Obesity, Aging, and Lung Metastases in Patients with Breast Cancer

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy.Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures.Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features.Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292–304. ©2018 AACR.

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Background: Patients with early HER2-positive breast cancer (BC) and residual disease after HER2-targeted neoadjuvant chemotherapy (NAC) are at high risk of recurrence. It is estimated that 10-30% of HER2-positive breast cancers change HER2 status after trastuzumab alone, but the effects of adding pertuzumab on this phenomenon and clinical outcomes remain unclear. We previously reported a high rate (~50%) of HER2 status change after HP in a small subset of patients. Herein, we present an updated analysis incorporating pathological review of additional cases.Methods: We identified patients with HER2-positive BC who received NAC with pertuzumab and trastuzumab (NAC-HP) followed by surgery at our institution between September 1, 2013 to November 1, 2019. Patients with HER2 status performed either at MSKCC or outside institutions were included. Change in HER2 status on residual disease from baseline was evaluated. We defined HER2 positivity as immunohistochemistry (IHC) IHC3+ or IHC0-2+ FISH amplified (ratio ≥ 2 or ratio < 2 and HER2 copy number ≥ 6 signals/cell). HER2-low was defined as IHC 1+ or 2+, FISH non-amplified. Disease free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Differences between patients with concordant and discordance HER2 status were assessed using the log-rank test.Results: Of 525 patients receiving NAC with HP, 229 (44%) patients had residual disease post NAC-HP. Among these 229 patients, 141 had both pre and post NAC-HP HER2 status available and were included in this analysis. HER2 status on biopsy specimens was determined at MSKCC in 35/141 (25%) and at external institution in 106/141 (75%). The majority of patients (84%) received dose-dense AC-THP; the remainder received TCHP or other HP-based regimens. Most (96%) of patients continued HP after surgery, and 2 patients received T-DM1. Of the 141 patients, 84/141(60%) were found to be HER2 concordant, while 57 (40%) were found to be HER2 discordant. In 13/57 (23%) patients, HER2 expression was lost (IHC 0), while in 44/57 (77%) patients, HER2-low profile was detected (IHC 1+ in 31, and IHC 2+, FISH non-amplified in 13). Further details are reported in the table. Patients with HER2 discordance after NAC-HP had similar survival outcome compared with patients who remained HER2 concordant (5-years DFS: 92.3% versus 88.7%, p=0.49 and 5-yr OS 93.6% versus 88.4%, p=0.70).Conclusions: In a single center cohort, discordant HER2 status after NAC-HP appeared frequently without statistically significant impact on survival outcome, although this finding may be due to the small size and hence low statistical power. Of these, HER2-low profile is the most frequent post treatment HER2 status change. This raises the possibility that patients with change in HER2 status may have heterogenous expression of HER2 at baseline, and HER2-loss or low sub-clones survive as residual disease due to the selection pressure of HP. Alternatively, anti-HER2 therapy may suppress HER2 expression in surviving cells. These findings could inform studies of tailored approaches in the post-neoadjuvant setting based on the biological profile of residual disease. Pre NAC-HP HER2 statusNPost NAC-HP HER2 statusNDiscordantN=57IHC 3+: 19IHC0: 4IHC1+: 9IHC2+ FISH not ampl: 6IHC 0-2+ FISH ampl: 38IHC0: 9IHC1+: 22IHC2+ FISH not ampl: 7Concordant N= 84IHC 3+: 59IHC 3+: 47IHC 0- 2+ FISH ampl: 12IHC 0-2+ FISH ampl: 25IHC 3+: 4IHC 0- 2+ FISH ampl: 21 Citation Format: Emanuela Ferraro, Anton Safonov, Hanna Y Wen, Edi Brogi, Mithat Gonan, Andrea V. Barrio, Pedram Razavi, Sarat Chandarlapaty, Shanu Modi, Andrew D. Seidman, Larry Norton, Mark E. Robson, Chau T. Dang. Clinical implication of HER2 status change after neoadjuvant chemotherapy with Trastuzumab and Pertuzumab (HP) in patients with HER2-positive breast cancer [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 P2-13-06.

AimsThe most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer.Methods and resultsUsing a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens—concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20–50 min at 55%–100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, −0.88 mL O2·kg−1·min−1; 95% confidence interval (CI): −3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg−1·min−1, P < 0.001).ConclusionThere was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

To characterise risk of anaphylaxis/hypersensitivity with intravenous pertuzumab plus trastuzumab (PH IV), the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) or concomitant chemotherapy to support potential administration of PH FDC SC by healthcare professionals outside clinics.A cumulative search for anaphylaxis/hypersensitivity (Roche Standard Adverse Event Group Terms) was performed for all pivotal trials cited in the current EMA P IV/PH FDC SC summaries of product characteristics: MBC: NCT00567190, NCT02402712; EBC: NCT01358877, NCT00545688, NCT00976989, NCT02132949, NCT03493854 and NCT03674112. Occurrence, incidence and severity of events were analysed and a time-trend analysis (by cycle) was performed.This analysis includes 4772 patients who received PH IV and/or PH FDC SC. Incidence of all-grade (grade ≥3) anaphylaxis/hypersensitivity events: 3-11% (≤2%) for PH IV MBC trials; 1-13% (0-3%) for PH IV EBC trials; and 2-3% (1%; not related to PH FDC SC) for PH FDC SC EBC trials. Discontinuations due to anaphylaxis/hypersensitivity were rare for PH IV (generally1% except two arms of TRYPHAENA: 1% and 3%); no discontinuations of PH FDC SC have been recorded so far. Time-trend analysis showed that most events were reported during the first 6-8 cycles with concurrent chemotherapy, with a decrease in later cycles (except MetaPHER).PH IV and PH FDC SC were well tolerated, with few grade ≥3 anaphylaxis/hypersensitivity events reported with PH IV and no grade ≥3 related events with PH FDC SC. Most events occurred during chemotherapy.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: The APT trial evaluated the activity of adjuvant paclitaxel and trastuzumab (TH) among patients with small, node negative HER2+ breast cancer. This regimen showed a 7-year invasive disease-free survival (iDFS) of 93%, a recurrence-free interval (RFI) of 97.5% with only four (1.0%) distant recurrences, and a 7-year overall survival (OS) of 95%. In this end-of-study analysis, we report the survival outcomes at 10 years and assess the role of HER2DX testing in predicting long-term outcomes with adjuvant TH. Methods: APT was a single-arm multicenter investigator-initiated phase II study in which patients with HER2+ breast cancer with tumors ≤3 cm and negative nodes (one single micrometastatic node allowed) received IV weekly paclitaxel (80 mg/m2) with IV weekly trastuzumab for 12 weeks, followed by IV trastuzumab for 9 months. The primary endpoint was 3-year iDFS. Here we report 10-year iDFS, RFI, breast cancer–specific survival (BCSS) and OS. In an exploratory analysis, the risk of recurrence was evaluated with the HER2DX genomic assay. Results: A total of 410 patients were enrolled from October 2007 to September 2010, of which 406 started the study treatment and were included in the intent to treat analysis. Median age at enrollment was 55 years (range, 24 to 85 years), and most patients (67%) had hormone receptor (HR)-positive disease. Fifty percent of patients had tumors 1.0 cm or smaller and only 9% of patients had tumors between 2 cm to 3 cm. Mean tumor size was 1.1 cm. After a median follow-up of 10.2 years (122 months), 36 iDFS events were observed, consistent with a 10-year iDFS of 89.7% (95% CI, 86.3%-93.1%). Ten-year iDFS was 90.2% (95% CI, 86.3%-94.3%) and 88.5% (95% CI, 82.4%-95.1%) for patients with HR-positive and HR-negative tumors at baseline, respectively. 10-year RFI was 96.8% (95% CI, 95.0%-98.7%), 10-year OS was 94.2% (95% CI, 91.6%-96.8%) and 10-year BCSS was 99.1% (95% CI, 98.1%-100.0%). Of the iDFS events observed in the trial, 6 were non-breast cancer related deaths and 9 were contralateral tumors, all but one locally found to be HER2-negative upon biopsy (Table 1). Among patients experiencing an iDFS event, 7 patients (1.7%) had distant recurrences, including 1 with a T2 tumor, 3 with a T1c tumor and 3 with a T1b tumor. At baseline, 6 of them had HR-positive disease, 1 had HR-negative disease, and 6 had high-grade disease. Upon biopsy of metastatic lesions, 5 of the 7 distant recurrences were locally found to be HER2+, 1 was HER2-negative and 1 had unknown HER2 status. HER2DX testing was conducted on available baseline archival tumor tissue and analyses of patients’ survival outcomes based on the HER2DX score will be presented. Conclusion: After 10 years of follow-up, adjuvant TH confirmed excellent long-term outcomes for small, node-negative HER2+ breast cancer, with a 10-year RFI of 96.8% and a 10-year BCSS of 99.1%. Table 1: iDFS events with adjuvant paclitaxel plus trastuzumab after 10.2 years of follow up Citation Format: Sara Tolaney, Paolo Tarantino, Noah Graham, Nabihah Tayob, Chau T Dang, Denise Yardley, Beverly Moy, Paul K. Marcom, Kathy S. Albain, Hope Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa Carey, Romualdo Barroso-Sousa, Michelle K. DeMeo, Molly K. DiLullo, Ann Partridge, Adrienne Waks, Clifford Hudis, Ian Krop, Harold Burstein, Aleix Prat, Eric Winer. Adjuvant Paclitaxel and Trastuzumab Trial (APT) for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Breast Cancer: final 10-year analysis [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 PD18-02.

Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [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 PD18-01.

Background: HER2 positive (HER2+) breast cancers harboring downstream MAPK or PI3K pathway alterations manifest persistent downstream signaling on anti-HER2 inhibitors with metastatic patients having worse outcomes on first line trastuzumab and pertuzumab (HP) therapy. However, HER2 antibody-drug conjugates (ADCs) are not as dependent upon potent signal transduction inhibition to exert their antitumor effects. To further investigate, we sought to determine whether MAPK and/or PI3K alterations affect the biologic or clinical outcomes of patients and models receiving HER2 ADCs. Methods: We performed prospective genomic sequencing using MSK-IMPACT on patients with advanced HER2+ breast cancer who received trastuzumab emtansine (T-DM1) in the metastatic setting between March 2013 and July 2021. We collected detailed information on clinical outcomes and correlates through our institutional IRB-approved retrieval process. HER2/ER/PR status at the time of metastatic recurrence were defined as per ASCO/CAP guidelines. Cox proportional hazard models were used to determine the association between MAPK and PI3K pathways alterations and progression-free survival (PFS) on T-DM1. Common mutations associated with outcomes were modeled in HER2+ breast cancer cell lines using short hairpin RNAs and CRISPR/Cas9, and the sensitivity to HER2 ADC was evaluated via cell proliferation and xenograft assays. Results: We identified 185 HER2+ breast cancer patients treated with T-DM1 at any line (median: 5) whose primary (N=65) or metastatic (N=120) tumor samples were sequenced. Median age was 55 (range: 20-87). The majority of the patients received T-DM1 in 2nd or 3rd line (52%) and received prior trastuzumab or HER2 TKI in metastatic setting (96%). 74/185 (40%) had de novo metastatic breast cancer and 119/185 (64%) had ER/PR+/HER2+ disease. Pathogenic activating alterations involving the MAPK pathway were observed in 14% of patients with the most frequent alterations being ERBB2 activating mutations (42%) and NF1 loss (34%). PI3K pathway alterations were identified in 42% of the patients, the majority being activating mutations of PIK3CA (87%). MAPK alterations were significantly enriched in the metastatic tumors compared to the treatment-naïve primaries (20% vs 3%, p=0.001), while PI3K alterations were not (44% vs 40%, p=0.6). To reduce the possible confounding resistance mechanisms induced by prior treatment, we restricted the survival analyses to patients who received T-DM1 up to 3rd line of therapy (N=100). On multivariable analysis adjusted for ER/PR status (positive vs negative), stage at the presentation of metastatic disease (de novo metastatic vs recurrence), treatment line and type of sequenced sample (primary vs metastatic), patients with MAPK (N=14) and PI3K (N= 38) alterations had similar PFS compared to wild type (HR 1.20, 95%CI 0.62-2.30, p=0.6 and HR 1.23, 95%CI 0.77-1.95, p=0.4, respectively). Similar results were found in the combined analysis including alterations in either pathway (N=48, HR 1.28, 95%CI 0.81-2.04, p=0.3). To verify the antiproliferative effect of HER2 ADCs on breast cancer cells with MAPK pathway activation, we depleted NF1 in a panel of HER2+ breast cancer cell lines. Consistently, MAPK-altered cell lines were sensitive to FDA-approved HER2 ADCs including trastuzumab deruxtecan (T-DXd). Conclusions: In contrast to H/P therapy, T-DM1 therapy was equally effective in tumors with downstream PI3K or MAPK alterations and wild type tumors. Expanded analysis on a larger cohort, including a subgroup of patients treated with novel HER2 ADCs such as T-DXd will be presented. The characterization of PI3K and MAPK pathways status in metastatic HER2+ breast cancer may inform prioritization of treatment options. Citation Format: Emanuela Ferraro, Anton Safonov, Yuan Chen, Charlie White, Antonio Marra, Mehnaj Ahmed, Barbara Acevedo, Chau T Dang, Shanu Modi, David B. Solit, Larry Norton, Mark E. Robson, Jorge Reis-Filho, Sarat Chandarlapaty, Pedram Razavi. Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive 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 P4-02-01.

Background: Neoadjuvant chemotherapy (NAC) is standard of care for the majority of patients with clinical stage II-III triple negative breast cancer (TNBC) and is considered in high-risk patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (-) tumors, with expected pathological complete response (pCR) rates of 40-60% and 10-12%, respectively. In HER2- patients with residual disease (RD) after NAC, there is limited data on rates of gain of HER2 amplification. The biological and clinical significance of this phenomenon is unknown and determining the best adjuvant therapy for these patients remains a challenge. We sought to determine the rate of HER2 gain in a cohort of consecutive patients with HER2- breast cancer (BC) treated with NAC. Methods: From 01/2021 to 12/2021, we identified patients with HER2- breast cancer treated with NAC followed by surgery at our institution. Patients who received neoadjuvant endocrine therapy were excluded. The rates of pCR (ypT0/is ypN0) and HER2 status pre- and post-NAC were assessed. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status on surgery specimens were internally determined for all patients using ASCO/CAP 2020 guidelines. ER-low was defined as ER expression by immunohistochemistry (IHC) 1-10%. Results: We included 256 patients, 130 (51%) HR+/HER2- [13/130(10%) ER-low] and 126 (49%) TNBC. Median age was 48 years (range 25-82) and the majority presented with clinical T2 (57%) and N1 (59%). Of 130 patients with HR+/HER2-tumors, 120 (92%) received dose-dense (dd) doxorubicin/cyclophosphamide-paclitaxel (AC-T). Of 126 TNBC patients, 46 (37%) received ddAC followed by carboplatin in combination with paclitaxel +/- pembrolizumab. Centralized HER2 status assessment on the core biopsy was performed in 22% of samples. Overall, pCR was achieved in 40% of TNBC and 11% of HR+/HER2-. Among the 192 patients with RD, the rate of HER2 gain was 8/192 (4%), including 3% (2/76) of TNBC and 5% (6/116) of HR+/HER2- patients. 7 of the 8 patients (88%) converted from IHC 1+ or 2+ fluorescence in situ hybridization (FISH) not amplified on core biopsy to IHC 2+ FISH amplified on the surgical specimen. In only 1 case, the HER2 status converted from IHC2+ FISH not amplified to IHC3+. 3/8 patients had multifocal disease. All 6 patients with HR+/HER2- BC and HER2 gain had high (>90%) ER expression (Table 1). All but one patient with HER2 gain received adjuvant anti-HER2 therapy. After a median follow-up of 10 months, no recurrence events occurred in this group.12 of the remaining 184 patients experienced a recurrence [11 distant recurrences (8 and 3, in the TNBC and HR+/HER2- groups, respectively), and there was 1 local event (localized chest wall recurrence) in the HR+/HER2- group]. Conclusions: At a single center, we found that in patients with HER2- BC treated with NAC, HER2 gain in patients with RD was uncommon and occurred more frequently in those with HR+ tumors. Analysis of a larger cohort is ongoing to corroborate these results. It is remains to be determined if this phenomenon represents a true HER2 status conversion or tumor heterogeneity. Table 1: Clinico-pathological characteristics of patients with HER2 gain on residual disease Citation Format: Emanuela Ferraro, Sonya Chew Minmin, Anton Safonov, Andrea V. Barrio, Shanu Modi, Andrew D Seidman, Hanna Y Wen, Edi Brogi, Mark E. Robson, Chau T Dang. Gain of HER2 Amplification in Patients with HR+/HER2- and Triple Negative Early Breast Cancer Treated with Neoadjuvant Chemotherapy [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 P4-02-14.

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.

Background: Guidelines recommend left ventricular ejection fraction (LVEF) assessments every 3 months for cardiotoxicity monitoring during human epidermal growth factor receptor 2 (HER2) targeted therapy. Evidence in support of this practice is lacking. Objectives: This study examines the association between adherence to cardiotoxicity surveillance guidelines and heart failure (HF) in HER2-positive breast cancer patients. Methods: A case-control study was performed in 53 patients who developed cardiotoxicity during HER2 targeted therapy, and 159 controls matched by age, anthracycline exposure, and year of treatment. Cardiotoxicity was defined as HF (New York Heart Association functional class III or IV) or cardiac death. Adherence to cardiotoxicity surveillance guidelines was ascertained from the beginning of HER2 targeted therapy to the diagnosis date of HF for cases or the corresponding timepoint for matched controls. Conditional logistic regression was used for case-control comparisons. Results: Eighty-one percent of cases and controls were previously treated with an anthracycline. Adherence to cardiotoxicity surveillance guidelines during the entire observation period or during the first 6 months of treatment was not associated with lower risk of HF. An LVEF

Background: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40–50 minutes per session), and volume (120–160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer. Methods: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO 2 peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO 2 peak (mL O 2 ·kg −1 ·min −1 ) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety. Results: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO 2 peak increased 0.6±1.7 mL O 2 ·kg −1 ·min −1 ( P =0.05) and 0.8±1.8 mL O 2 ·kg −1 ·min −1 ( P =0.07) in LET and NLET, respectively, compared with attention control. Change in VO 2 peak ranged from −2.7 to 4.1 mL O 2 ·kg −1 ·min −1 and from −3.6 to 5.1 mL O 2 ·kg −1 ·min −1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO 2 peak responders (ie, Δ ≥1.32 mL O 2 ·kg −1 ·min −1 ). NLET improved all patient-reported outcomes compared with attention control. Conclusions: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01186367.

Background: According to several estimates, African American women are 40% more likely to die from breast cancer than white women in the United States. Proposed explanations for this disparity include differential socioeconomic factors and access to care, however some studies have raised the possibility that variation in tumor biology is a contributing factor. Methods: We prospectively sequenced primary and metastatic breast cancer tumors and their matched normal DNA using the MSK-IMPACT assay. We performed gene enrichment analyses to identify the oncogenic mutations and copy number alterations that were more frequent in patients who self-identified as African American or black (AA/B) compared with patients who self-identified as non-Hispanic white (NHW). Detailed clinicopathologic variables were collected for the full cohort. Mann-Whitney U test, Fisher’s exact test, and multivariate binomial regression models were used for statistical analyses. Results: Genomic profiling was performed on 339 tumors from 301 AA/B patients (44.6% metastatic), and 2,607 tumors from 2,248 NHW patients (48.5% metastatic). Age of AA/B and NHW patients at diagnosis was similar (51.5 vs. 52.8 years, p = 0.065). However, AA/B patients were more likely to be pre- or peri-menopausal at diagnosis (51.6 vs. 44%, p = 0.013), have triple-negative disease (26.5 vs. 13%, p < 0.001), and have higher stage at diagnosis (p = 0.024). Of note, invasive lobular carcinomas were significantly less frequent in AA/B patients compared to NHW (5.9 vs. 14.5%; p < 0.001), a trend that persisted when controlling for receptor subtype. In the unadjusted analysis, AA/B women were more likely to have TP53 mutations (53.4 vs. 36.5%; q < 0.01) and NF1 loss of function mutations (9.9% vs. 3.7%; q < 0.01), and less likely to have CDH1 mutations (6.3% vs. 15.4%; q < 0.01) and PIK3CA mutations (25.7 vs. 35.6%, q = 0.017). However, in a multivariate analysis adjusted for receptor subtype, histology, and sample type (primary vs. metastatic), NF1 was the only gene found to be more commonly mutated in AA/B women (odds ratio: 2.84; 95% CI: 1.73 - 4.08, q < 0.01). Focusing specifically on ER+/HER2- disease, AA/B women were more likely to have mutations in TP53 (31.6% vs. 24.6%), NF1 (7.7% vs. 3.1%) and FGFR1 amplification (21.4% vs. 13.1%), and less likely to have mutations in CDH1 (9.2% vs. 18.8%) or PIK3CA (29.6% vs. 39.6%), however these results did not retain statistical significance when adjusted for multiple comparisons. In triple-negative breast cancer patients, TP53 was mutated at equal rates in AA/B and NHW patients (88.9% vs. 85.9%; p = 0.59), and there was a numerically higher frequency of NF1 mutations in AA/B patients (11.1% vs. 5%). There was no significant difference in tumor mutational burden between AA/B and NHW women (4.24 vs. 4.87; p = 0.19), and no difference in the frequency of microsatellite instability (defined as MSISensor score > 10, 0.9% vs. 0.5%; p = 0.44). Conclusions: In this large clinico-genomic analysis, as previously reported, AA/B patients were more likely to have the clinical hallmarks of aggressive disease, as defined by triple-negative subtype, higher stage, and premenopausal status at diagnosis. Our analysis demonstrated trends towards enrichment for some of the genomic alterations previously identified to be associated with poor outcome in the AA/B population, however, after controlling for the aforementioned clinical factors, breast cancer in AA/B did not differ significantly from breast cancer in NHW in terms of their driver genomic alterations, MSI or tumor mutation burden. Further studies are required to fully characterize the genomics of breast cancer in AA/B women, which may play a role in larger efforts to equalize the disparities observed in this population. Citation Format: Cristian Serna-Tamayo, Joshua Z Drago, Carlos Dos Anjos, Joshua Herbert, Fresia Pareja, Shanu Modi, Komal Jhaveri, Chau Dang, David B Solit, Larry Norton, Mauricio Scaltriti, Jorge S Reis-Filho, Sarat Chandarlapaty, Mark E. Robson, Pedram Razavi. The genomic landscape of breast cancer in African American women [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 P2-10-01.

Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT 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 P2-13-02.

Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting followed by adjuvant anti-HER2 therapy. Here we report the invasive disease-free survival (iDFS) rate, defined as the time from surgery to the first documented event of ipsilateral invasive local recurrence, ipsilateral locoregional invasive recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2016. Charts were analyzed for pt demographics, stage of breast cancer, surgical data, pathologic complete response (pCR)(ypT0/is ypN0) and information on systemic therapy. Results: Charts from 236 pts were reviewed. One patient was excluded as she developed metastatic disease during NAC and did not have surgery. Median follow up was 3.8 years. Median age was 49 years (range 26-79 years). Of 235 pts, 215 (91%) had operable breast cancer (T1-3, N0-1, M0) of which 10 (4%) had clinical stage I disease (T1N0)]; 225 (96%) had stage II/III (T2-4d N0-3 M0); 18 (8%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 9 (3.8%) had inflammatory breast cancer (T4d, any N, M0). 153 (65%) and 82 (35%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of ≥ 2.0. Median number of preoperative HP cycles was 5.5 (range 1-9). 121pts (51%) underwent mastectomy, 113 pts (48%) underwent lumpectomy, 1 patient underwent axillary dissection only. Out of 235 evaluable pts, 146 (62%) had pCR; 80/153 (52%) with HR-positive and 65/82 (78%) with HR-negative diseases had pCR, respectively. After a median follow-up of 3.8 years, there were 21 iDFS events and 10 OS events (n=9-Breast cancer, n=1-Acute Myeloid Leukemia). The 3-year iDFS was 91% (95% C.I. 88-95%) for all, 94% (95% C.I. 90-98%) for pts w/ pCR, and 87% (95% C.I. 80-95%) for pts w/ non pCR (p-value=0.051). The 3-year OS was 96% (95% C.I. 94-99%) for all, 98% (95% C.I. 95-100%) for pts w/ pCR, and 93% (95% C.I. 88-99%) for pts w/ non pCR (p-value=0.12) Conclusions: At our single center experience, the iDFS and OS for patients who received neoadjuvant ddACTHP followed by adjuvant anti-HER2 treatment was 91% and 96%, respectively. Patients with pCR had better outcomes than those with residual disease. Citation Format: Jasmeet C Singh, Sujata Patil, Larry Norton, Mark Robson, Chau Dang. Disease free survival rate with dose dense Doxorubicin and Cyclophosphamide followed by weekly Paclitaxel with Trastuzumab and Pertuzumab (ddACTHP) in patients with HER2-positive early stage breast cancer: A single institution experience [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 P2-16-10.

Background: The current standard of care for patients achieving a pCR after HER2-targeted therapy plus chemotherapy in the neoadjuvant setting is to continue HER2-targeted therapy in the adjuvant setting. The aim of this exploratory data analysis is to report the risk of recurrence and death after neoadjuvant systemic therapy in Roche-sponsored neoadjuvant trials in patients with HER2-positive early breast cancer who achieved a pCR. Methods: Data from the HannaH (NCT00950300), NeoSphere (NCT00545688), TRYPHAENA (NCT00976989), BERENICE (NCT02132949), and KRISTINE (NCT02131064) studies were pooled. Neoadjuvant → adjuvant therapeutic regimens analyzed were trastuzumab → trastuzumab (H→H), pertuzumab plus trastuzumab → trastuzumab (PH→H), and pertuzumab plus trastuzumab → pertuzumab plus trastuzumab (PH→PH). pCR was defined as the absence of residual invasive cancer in the resected breast specimen and in the axillary lymph nodes (ypT0/Tis ypN0) after neoadjuvant systemic therapy. Event-free survival (EFS) was defined as the time from the date of randomization to the date of disease recurrence or progression (local, regional, distant, or contralateral) or death due to any cause. EFS rates were estimated using the Kaplan-Meier method. A Cox regression model was used to explore factors associated with EFS. Results: 1764 patients were included in the analysis. The median duration of follow up was shorter in the PH→PH group compared to the PH→H and H→H groups (Table). Overall, patients with a pCR had an increased EFS probability compared to those with residual disease (unadjusted hazard ratio=0.33; 95% confidence interval [CI]: 0.25– 0.43]), and this was maintained in patients stratified by hormone receptor status and disease stage. The 3-year EFS rates in patients who achieved a pCR were 87% (95% CI: 82%–90%) in the H→H group, 92% (95% CI: 87%–95%) in the PH→H group, and 95% (95% CI: 90%–97%) in the PH→PH group. Conclusions: Overall, patients who attained a pCR have a better long-term outcome compared to those with residual disease, regardless of ER status or clinical stage. Some patients who achieved a pCR still had a risk of relapse. A limitation of this exploratory data analysis was the smaller number of patients with stage III disease at baseline and shorter follow-up in the PH→PH group compared to the other groups. Overall(N=1764)H→H (HannaH; NeoSPHERE)(n=703)PH→H (NeoSPHERE; TRYPHAENA)(n=439)PH→PH (BERENICE; KRISTINE)(n=622)Median Duration of Follow-up (months)42.067.961.122.3Disease StageStage II934 (52.9)285 (40.5)204 (46.5)445 (71.5)Stage III806 (45.7)397 (56.5)235 (53.5)174 (28.0)Hormone Receptor StatusPositive783 (44.4)328 (46.7)223 (50.8)232 (37.3)Negative963 (54.6)372 (52.9)215 (49.0)376 (60.5)Unknown18 (1.0)3 (0.4)1 (0.2)14 (2.3)pCR status773 (43.8)236 (33.6)185 (42.1)352 (56.6)Type of recurrence in patients who achieved a pCRDistant recurrence41 (5.3)26 (11.0)10 (5.4)5 (1.4)Local recurrence17 (2.2)12 (5.1)5 (2.7)0Regional recurrence6 (0.8)3 (1.3)2 (1.1)1 (0.3)New contralateral breast cancer2 (0.3)2 (0.8)00 Citation Format: Sandra M Swain, Harrison Macharia, Javier Cortes, Chau Dang, Luca Gianni, Sara Hurvitz, Christian Jackisch, Andreas Schneeweiss, Dennis Slamon, Pinuccia Valagussa, Yolande du Toit, Dominik Heinzmann, Adam Knott, Chunyan Song, Patricia Cortazar. Risk of recurrence and death in patients with early HER2-positive breast cancer who achieve a pathological complete response (pCR) after different types of HER2-targeted therapy: A retrospective exploratory 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 P1-18-01.

Breast cancer treatment can impact not only short-term health but may also affect longer-term quality of life (QOL).To describe and evaluate factors associated with diminished QOL following completion of active treatment.This was a secondary analysis of a randomized clinical trial included patients with lymph node-positive or high-risk lymph node-negative breast cancer who had undergone definitive surgery and were enrolled in ECOG-ACRIN E5103, a multisite phase 3 trial. A survey was administered 18 months after enrollment to patients enrolled between January and June 2010. Final analysis of the data took place from March to December 2021.Patients received adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo.QOL and health status assessed with the EuroQol 5-Dimension 3-Levels (EQ-5D-3L), EQ-visual analog scale (EQ-VAS), and the Functional Assessment of Cancer Therapy-Breast Cancer, with arm subscale (FACT-B+4). Groups were compared by Fisher exact test, Wilcoxon rank sum, or Kruskal-Wallis test. Multivariable linear regression was used to assess factors independently associated with FACT-B scores.Data at 18 months were available from 455 of 519 patients (87.7%) enrolled in the trial. Median (range) age at enrollment was 52 (25-76) years. No differences in QOL (median [range] FACT-B scores: group A, 123 [67-146]; group B, 114 [54-148]; group C, 117 [42-148]; P = .23) or health status (median [range] EQ-5D-3L index scores: group A, 0.83 [0.28-1.00]; group B, 0.83 [0.20-1.00]; group C, 0.83 [0.17-1.00], P = .80; median EQ-VAS: group A, 85 [20-100]; group B, 85 [0-100]; group C, 85 [0-100]; P = .79) were observed across treatment groups; results for subsequent analyses were therefore reported irrespective of primary treatment. Overall, half of patients (258 of 444 [58%]) reported at least some pain or discomfort; 170 (38%) reported symptoms of anxiety or depression. In multivariable analyses, mastectomy with radiation (vs breast conserving surgery) and Asian, Black, or American Indian or Alaska Native race (vs White race) were associated with lower QOL (mastectomy with radiation: coefficient: -5.5; 95% CI, -10.1 to -0.9; Asian, Black, or American Indian or Alaska Native race: coefficient: -7.3; 95% CI, -13.2, -1.4).In this study, the addition of bevacizumab to chemotherapy was not negatively associated with QOL at 18 months. A substantial proportion of participants reported problems related to pain or discomfort and anxiety or depression, demonstrating persistent consequences for physical and psychosocial well-being in this heavily treated population. Many problems reported are amenable to intervention, underscoring the need for timely referral to supportive resources, especially for women of color and those who have more extensive local therapy.ClinicalTrials.gov Identifier: NCT00433511.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA damaging agents such as radiation and anthracycline chemotherapies induce delayed cardiac inflammation following therapy due to activation of cGAS and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING-signaling in mice inhibits DNA damage induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA damaging therapies and effectively mitigates cardiotoxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Context.— The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline. Objective.— To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results. Design.— We retrospectively reviewed HER2 fluorescence in situ hybridization (FISH) data (HER2/CEP17 ratio and average HER2 copy number per cell) of HER2 immunohistochemistry–equivocal (2+ or 1+ to 2+) breast cancers at our center between January 2014 and May 2018 and compared HER2 FISH results according to 2013 and 2018 guidelines. Results.— A total of 1666 HER2 FISH results from 1421 patients with equivocal HER2 immunohistochemistry were reviewed. Based on the 2013 guideline, HER2 FISH results were amplified in 346 cases (20.8%), equivocal in 242 (14.5%), and nonamplified in 1078 (64.7%). Using the 2018 guideline, 258 cases (16%) were reclassified, including 242 previously equivocal test results (15%) and 16 previously positive results (1%) reclassified as negative. The subset of 2013 HER2-equivocal and 2018 HER2-nonamplified cases with HER2/CEP17 ratio lower than 2.0 and average HER2 copy number 4.0 or higher and lower than 6.0 showed higher incidence of micropapillary morphology compared with HER2-amplified cases. Despite most patients in this group not receiving HER2-targeted treatment, 96% had no evidence of disease at follow-up. Conclusions.— The 2018 guideline eliminated HER2 FISH–equivocal cases by reclassifying HER2-equivocal cases and cases with nonclassical amplification without HER2 overexpression as HER2 negative. As a consequence, we observed a considerable increase in HER2 FISH–negative cases and a slight decrease in HER2 FISH–positive cases.

Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local–regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan–Meier method. Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4–96.2), and LRR-free survival was 98.6% (95% CI 97.4–99.8). LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Background Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics. Patients and methods The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out. Results Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. Conclusion Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome. Clinical trial registration clinicaltrials.gov identifier: NCT00542451.

Purpose HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. Methods Patients with stage I–IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40–49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. Results Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. Conclusion This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population. Electronic supplementary material The online version of this article (10.1007/s10549-019-05191-2) contains supplementary material, which is available to authorized users.

Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with > G 3 diarrhea in > 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented. Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-30.

Background: In CALGB 40601 (Alliance, NCT00770809), a neoadjuvant phase III trial of paclitaxel and trastuzumab with or without lapatinib for 12 weeks for patients with HER2-positive breast cancer, 33% of pretreatment tumors were Luminal A subtype, however, 69% of post-treatment samples with residual disease were Luminal A subtype. In addition, 71% of Luminal B (12/17) and 67% of HER2-Enriched (6/9) tumors changed into Luminal A, while 80% of Luminal A (20/24) remained Luminal A (Carey et al. J Clin Oncol. 2016). It is not known whether this shift to Luminal A was transient or permanent. Methods: We selected matched pairs of pre- and post-treatment 40601 samples with tumor purity >10% based upon DNA analyses to ensure all samples contained tumor. PAM50 intrinsic subtyping was applied to the 40601 samples gene expression data using a two-step normalization process based on The Genome Cancer Atlas, and PAM50 training set. In addition, a HER2-enriched expression subtype patient-derived xenograft (PDX) tumor called WHIM35, was studied and was either untreated (n=10), or treated with lapatinib at 220 mg/kg for 1 week (wk) (n=5), for 2 wks (n=8), or for 3 wks (n=4). We also treated WHIM35 tumors with lapatinib for 2 wks (on) and then removed laptinib for 1 wk (off) (n=6), or for 2 wks on and 2-4 wk off (n=6), and finally for 3 wks on, and 1 wk off (n=3). PAM50 intrinsic subtyping was applied to the PDX gene expression data and subtype assessed as well as a genomic-based proliferation score. ANOVA p-values were calculated by comparing median values across all gene signature or correlation scores. Results: We found 10 pairs of 40601 samples that kept their tumor purity values, however, their subtype changed to Luminal A after treatment (i.e., in the residual disease), and in these cases no minor tumor subclone became a dominant clone in the post treatment sample. Pretreatment subtypes were 6 Luminal B, 3 Luminal A, and 1 HER2-enriched. The tumor purity values did not change after the treatments, but correlation to Luminal A was significantly higher (p=0.01), while correlation to HER2-enriched (p=0.004) and proliferation signature scores (p=0.003) were significantly lower in the post-treatment samples. Among the WHIM35 PDX tumors, one sample changed its subtype from HER2-enriched to Luminal A after the lapatinib treatment and the rest remained HER2-enriched, suggesting environmental differences between patient samples and the PDX model. However, correlation to Luminal A was significantly higher in all lapatinib treated WHIM35 samples (p=8.3e-12), and notably went back to the initial low levels just one week after removing lapatinib. Likewise, correlation to HER2-enriched (p=1.2e-10) and proliferation signature scores (p=6.2e-12) also got lower while treated with lapatinib, but went back to the initial levels after cessation of treatment. Conclusions: Our findings suggest that the apparent subtype change during HER2-targeting therapy is not permanent, but is more likely a transient state change from a HER2-enriched subtype into a more Luminal A-like state. When we plan additional treatment strategies using residual disease phenotypes, it may not be clear what is the true subtype of the sample due to this inherent plasticity. Citation Format: Tanioka M, Parker JS, Henry LN, Tolaney S, Dang C, Krop IE, Harris L, Polley M, Berry DA, Winer EP, Carey LA, Perou CM. Transient state change, but not permanent subtype change, after HER2-targeted therapy for HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-04.

Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.Patients with HER2-positive breast cancer and asymptomatic LVEF decline to 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death.Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29).Continuation of trastuzumab after an asymptomatic LVEF decline to 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Background Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. Materials and methods In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. Results From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. Conclusion With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. Implications for practice The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

12100 Background: Rash associated with increased peripheral eosinophils develops in approximately 50% of metastatic breast cancer patients receiving alpelisib. Antihistamines and corticosteroids have limited benefit. Refractory rash may lead to decreased dose intensity and affect clinical outcome. Benralizumab is an anti-IL-5Rα chimeric monoclonal antibody that depletes peripheral eosinophils and has demonstrated benefit in eosinophilic asthma and hypereosinophilic syndrome. We investigate the efficacy and safety of benralizumab for the treatment of alpelisib rash. Methods: We performed a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab in cancer patients who developed CTCAE grade 2/3 skin events resulting from immunotherapy or targeted therapies with absolute blood eosinophil counts of ≥300/mcl. While remaining on culprit drugs, patients were treated with benralizumab 30mg once every 4 weeks for the first 3 doses followed by once every 8 weeks for 3 additional doses (approved dosing for eosinophilic asthma). Primary endpoint was clinical response measured as reduction in CTCAE grade 2/3 skin event to grade ≤1 by week 4. Secondary endpoints were patient quality of life (QoL) measured by skindex16, safety data, need for supportive oral corticosteroids, and changes in cytokines and eosinophil biomarkers. This interim analysis focuses on patients with PIK3CA-mutant metastatic breast cancer receiving alpelisib. Results: Between September 16th 2020 and January 1st 2022, we enrolled 10 metastatic breast cancer patients with grade 2/3 rash attributed to alpelisib (5 pts with G3). All patients had a reduction of rash to grade ≤1 (n = 10, p < 0.0001), and a decrease in peripheral absolute eosinophils (mean 500/mcl to 0, p < 0.0001). Of these, 6 patients had been on prophylactic oral antihistamines and 2 had oral steroid coadministration. QoL significantly improved (Skindex16 mean score 58 to 16, p = 0.0001) and eosinophils in skin histology decreased per HPF (mean 6.25 to 0.25, n = 8, p = 0.2) by week 4. An increase in IL-5 > 600% and reduction IL-6 and TNF-α > 50% were reported by week 4 and 8. Grade 1/2 mucositis in 4 patients were reported as adverse events. Conclusions: Our findings suggest that benralizumab is safe and effective for the treatment of grade 2/3 rash with eosinophilia related to alpelisib in patients with breast cancer. A reduction in rash severity was evidenced in all patients, along with improved QoL. Larger controlled studies are in development to evaluate the efficacy of benralizumab for the prevention of alpelisib rash. Clinical trial information: NCT04552288.

1515 Background: Standard of care for HER2+ early/first-line metastatic BC (EBC/MBC) is P + H and concurrent chemotherapy (CT); PH FDC SC offers faster, more convenient admin vs intravenous (IV) P + H. COVID-19 has caused unprecedented strain on healthcare systems and disruption to cancer care; treatment (Tx) at home may: enable pts to continue cancer Tx; reduce exposure to COVID-19; free up hospital resources. This study’s main objectives: to enable continuity of care during COVID-19; to assess safety of PH FDC SC given at home. Methods: This is an ongoing single-arm, hybrid, decentralized clinical trial (NCT04395508). Pts with HER2+ EBC/MBC who completed concurrent CT with P + H IV and are receiving/about to receive maintenance P + H IV, PH FDC SC, or H SC are switched to PH FDC SC given at home by a home health nursing provider (HHNP) until disease progression, unacceptable toxicity, pt withdrawal, or physician recommendation (pts with EBC will complete ≤18 cycles). The study endpoint is safety. A subset of pts took part in HARRIET, a substudy of at-home cardiac surveillance with artificial intelligence-guided cardiac ultrasound and optional 6L ECG acquired by an HHNP. Results: Data for 114 pts (1 male) were available at cutoff (Jan 19, 2022): 18 (16%) completed Tx; 20 (18%) discontinued; 76 (67%) remain on study; 79 (69%) had a COVID-19 vaccine while on study. Median age was 49 years; pts were balanced between EBC (n = 55, 48%) and MBC (n = 59, 52%); received a median of 6 (EBC) and 8 (MBC) cycles; and were from metropolitan (n = 109), urban (n = 4), and rural (n = 1) areas. 11 pts tested COVID-19-positive during the Tx phase: 8 continued Tx after appropriate COVID-19 Tx and/or quarantine. Safety is summarized in the table. No new adverse events (AEs) emerged due to home admin. AEs of special interest were grade (gr) 1–2: admin-related reactions (n = 76, 67%), hypersensitivity (n = 5, 4%), cardiac dysfunction (n = 4, 4%), except 1 case of gr ≥3 diarrhea. AEs leading to study Tx discontinuation or interruption/dose reduction occurred in 3 (3%) and 15 (13%) pts. A subset of 7 pts completed at-home cardiac surveillance testing; quantitative assessment of left ventricular ejection fraction was feasible in 3 (43%); 5 (71%) preferred at-home surveillance to clinic. Conclusions: In this preliminary analysis, safety of PH FDC SC at home was consistent with the established P + H safety profile, indicating that PH FDC SC at home is a viable option for continuing BC care during and beyond COVID-19. Clinical trial information: NCT04395508. [Table: see text]

12090 Background: There is currently no way to reliably predict which patients undergoing therapy for breast cancer will develop cardiotoxicity. An early biomarker of cardiotoxicity could provide opportunity for intervention prior to the appearance of gross abnormalities on echocardiogram (ECHO). A droplet digital PCR (ddPCR) assay for circulating cell-free DNA (cfDNA) can detect cfDNA released from dying cardiomyocytes with high sensitivity by differentiating cfDNA of cardiomyocyte origin based on the pattern of methylation specific to the cell type. Circulating cfDNA of cardiac origin was tested as an early biomarker of toxicity in patients who underwent breast cancer treatment while closely monitoring cardiac function in a prospective clinical trial. Methods: A cardiomyocyte methylation-specific quantitative ddPCR assay was tested in plasma samples from 29 patients who were part of a larger prospectively enrolled cohort of women who received anthracyclines and trastuzumab for HER2-positive breast cancer. Blood samples were tested from prior to doxorubicin and cyclophosphamide (AC) chemotherapy, two months later after completing AC and prior to trastuzumab, and every 3 months to 12 months post-treatment. Patients were assessed for clinical cardiotoxicity, defined as heart failure (NYHA class III/IV) or significant EF decline (> = 10% to below 53% or > = 16%) until completion of cancer therapy. The maximum detected level of cardiac cfDNA (copies per 500 µL plasma) was compared between those who experienced cardiotoxicity and those who did not by two-sided T-tests. Results are reported as mean +/- standard deviation. Results: At baseline, cardiac cfDNA levels were low (mean 1.1 +/- 2.4 copies). Of 29 patients, five developed clinical cardiotoxicity. The maximum number of cfDNA copies at any time point was elevated in patients who experienced cardiotoxicity compared to those who did not (mean of 20.6 +/- 7.3 copies versus 9.3 +/- 9.8 copies, p = 0.0216). Of the patients with cardiotoxicity, elevated cfDNA of greater than 10 copies was detected an average of 3.6 +/- 2.5 months prior to the onset of clinical cardiotoxicity. Conclusions: Methylation specific cardiac cfDNA shows promise as an early indicator of cardiotoxicity in patients treated with anthracyclines in this pilot study. A previously reported analysis in the levels of seven other biomarkers including high-sensitivity troponin I and NT-proBNP pre- versus post-treatment in the full cohort of 80 patients did not show any statistically significant associations with the development of cardiotoxicity, suggesting that cardiac cfDNA may be uniquely informative. Clinical trial information: NCT02177175.