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Purpose: The ATEMPT trial sought to determine if adjuvant T-DM1 (every 3 wks for 1 yr) for Stage I HER2 positive breast cancer is better tolerated than TH (paclitaxel weekly x 12 wks with 1 yr of trastuzumab). Here we compare patient-reported outcomes (PROs) including quality of life (QOL), specific symptoms, and work productivity between the two treatments over time. Patients and Methods: English-speaking patients were randomized (3:1) to T-DM1 or TH, and completed PRO assessments at baseline (day 1), 3 wks, 12 wks, and 6, 12, and 18 mos after initiation of treatment. Surveys included the FACT-B, Patient-Neurotoxicity Questionnaire (PNQ), Rotterdam Symptom Checklist (RSCL), Alopecia Patient Assessment, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Results: 469/497 (94%) patients (363 on T-DM1, 106 on TH) completed surveys at any timepoint, ranging from 100% at baseline to 79% at 18 mos. Median age was 56 yrs (range 23-85). There were different patterns of deterioration and recovery seen over time in each group for QOL and other relevant symptoms. Compared with the T-DM1 group, the TH group had significantly lower mean total FACT-B scores, indicating poorer QOL from baseline to 12 weeks (p<0.001 for each timepoint); mean scores were similar between the groups at 6 and 12 mos, and significantly worse again in the TH group at 18 mos. The greatest mean change from baseline, and lowest FACT-B scores overall were reported in the TH group at 12 weeks. Moderate to severe sensory neuropathy was 8% at 12 weeks for patients receiving T-DM1 and reached its highest level of 15% by 18 mos. In comparison, moderate to severe sensory neuropathy was 35% at 12 weeks and 26% at 18 mos for patients on TH (p<0.001 at 12 weeks and p=0.018 at 18 mos). Hair loss at week 12 was 13% on T-DM1 compared to 77% on TH (p<0.001). Mean physical symptom distress was greater for TH at baseline, 3 and 12 weeks, and greater for T-DM1 at 1 year, with greatest symptom distress reported by the TH group at 12 weeks. Psychological distress was greatest for both groups at enrollment, though significantly greater with TH than T-DM1 at baseline, 12 weeks and 18 mos (groups were similar at 6 and 12 mos). There was limited impact on activity level impairment in both groups. Rates of employment were lowest for the TH group at 12 weeks (49% TH vs. 61% T-DM1, p=0.074) with significant differences seen at 3 and 12 weeks for percent work time missed due to health treatment, percent impairment while working, percent overall work impairment, and percent activity impairment, all favoring T-DM1. Conclusion: PROs differ between patients with Stage I HER2 positive breast cancer treated with T-DM1 vs. TH. T-DM1 treated patients had better QOL, less neuropathy and hair loss, and better work productivity, particularly during the first 12 weeks of treatment, and importantly, differences persist with longer-term follow-up. Citation Format: Ann Partridge, Yue Zheng, Shoshana Rosenberg, Richard Gelber, Shari Gelber, William Barry, Chau Dang, Denise Yardley, Steven Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna Gadi, Michael Constantine, Kit Cheng, Frederick Briccetti, Bryan Schneider, Merrill Garrett, P. Kelly Marcom, Kathy Albain, Patricia Defusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel Jankowitz, Michelle DeMeo, Harold Burstein, Eric P. Winer, Ian Krop, Sara Tolaney. Patient reported outcomes from the adjuvant trastuzumab emtansine (T-DM1) vs. paclitaxel + trastuzumab (TH) (ATEMPT) trial (TBCRC 033) [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 PD10-02.

Pathologic complete response (pCR) after neoadjuvant chemotherapy is associated with improved survival in locally advanced and inflammatory breast cancer. Neoadjuvant sunitinib + paclitaxel followed by doxorubicin + cyclophosphamide with G-CSF therapy resulted in a 27% pCR rate in this single-arm, phase II trial. ER + patients had higher response rates (64%) using the CPS + EG score and pCR, suggesting promising incremental benefit. Introduction: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. Methods: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S + T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m 2 IV weekly ×12 followed by doxorubicin 24 mg/m 2 IV weekly + cyclophosphamide 60 mg/m 2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). Results: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER + disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders.

The goal of precision medicine is to match the right drug to the right patient. However, every individual cancer carries a unique and complex mosaic of genetic and molecular changes making it difficult to identify the right drug based solely on genomic analysis. We developed a CLIA-certified functional drug assay (PARIS® test) for solid tumors which provides an actionable report of tumor derived organoid sensitivities to targeted, endocrine and chemotherapy agents as a tool for clinical therapeutic decisions. Objectives:1.To establish the concordance between organoid drug sensitivity with well-known genomic or immunohistochemical IHC biomarkers 2.To correlate organoid drug sensitivity with clinical outcomes.Methods: From 2015 to 2020, organoids from 410 tumor samples were subjected to functional testing at SEngine Precision Medicine, including 61 breast tumor samples from 48 patients. Fresh samples of tumor cells from core biopsies, surgical excisions, or from fluids arrived <48 hrs following collection and were cultured as 3D organoids. Samples were evaluated using a multi-dose drug response format with a library of up to 130 oncology drugs. Drug sensitivity was quantified using the SPM score (1-15) that combines sensitivity and personalization of each patient’s response relative to a reference population. Known genomic anchors and IHC subtypes were compared to drug sensitivity to determine concordance.Results: 61 breast cancer samples from 48 patients were analyzed. The median age of patients was 53.4 (r26-76). 65 drugs on average were tested per patient with a mean turnaround time of 21 days (r9 -37). A mean of 6 drugs per patient were identified as top scoring sensitive drugs. In 42 patients with genomic or IHC data, we found high concordance of drug sensitivity with known biomarkers (e.g., HER2+ or ERBB2 amplification:HER2 or EGFR inhibitor, BRCA1 mutation: PARP inhibitor, FGFR1-2 mutation or amplification: FGFR inhibitor, PIK3CA mutation:PI3K inhibitor), measured as sensitivity to the cognate targeted drugs. For PIK3CAmut we found an 80% correlation of organoid sensitivity to alpelisib and taselisib. For HER2/ EGFRinh the correlation was 100%. We also found organoid sensitivity to targeted agents in the absence of known genomic or IHC biomarkers, for example tamoxifen and fulvestrant sensitivity in triple negative breast tumors, or HER2 inhibitor sensitivity in HER2 IHC negative tumors or PARP inhibitor sensitivity with BRCA2 variant of unknown significance (VUS). In a cohort of 18 analyzable patients, the retrospective and prospective correlation between organoid based drug sensitivity and clinical outcome was >90%.Conclusions: Organoid based drug testing exhibits strong concordance with genomic or IHC biomarkers and clinical response. In addition, functional testing identifies candidate therapies in patients lacking biomarkers and can nominate variants of unknown significance as candidate biomarkers. This study highlights the utility of functional assays to support clinical decision making in a genetically heterogenous cancer such as breast cancer. Citation Format: Astrid Margossian, Anne Richardson, Madison Pollastro, Michael Churchill, Franz Schaub, Shalini Pereira, Payel Chatterjee, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Alex Federation, G. Adam Whitney, Hallie Swan, Trevor Ainge, Robert Diaz, Natasha Hunter, Eric Gamboa, Chris Kemp, Vijayakrishna Gadi, Carla Grandori. Clinical and genomic correlation of a CLIA certified organoid based functional test in breast cancer patients [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 PS4-01.