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  • American Association for Cancer Research (AACR)  (14)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD18-02-PD18-02
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. GS2-05-GS2-05
    Abstract: Background The updated combined SOFT+TEXT analysis, after 9 years median follow-up (MFU), revealed that adjuvant E+OFS vs T+OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI) but not overall survival (OS) in premenopausal women with HR+ early BC (Francis et al NEJM 2018). Given the high rate of OS in both arms and the long-term risk of relapse in HR+ BC, continued follow-up is key to assessing treatment benefit. We report a planned update analysis including OS with database lock of May 2021, after 13 years MFU.. Methods TEXT and SOFT enrolled premenopausal women with HR+ early BC from November 2003 to April 2011 (2660 in TEXT, 3047 in SOFT intention-to-treat (ITT) populations). TEXT randomized women within 12 weeks of surgery to 5 years E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5 years E+OFS vs T+OFS vs T alone, within 12 weeks of surgery if no CT planned, or within 8 months of completing (neo)adjuvant CT. Both trials were stratified by CT use. For the combined analysis of E+OFS vs T+OFS, the primary endpoint was DFS defined as invasive local, regional, distant recurrence, contralateral BC, second malignancy, death. Secondary endpoints included invasive breast cancer-free interval (BCFI), DRFI and OS.. Results: At database lock there were 953 DFS events and 473 deaths among 4690 pts assigned to T+OFS or E+OFS. In the ITT population, DFS, BCFI and DRFI outcomes for pts assigned E+OFS (n=2346) continued to be significantly improved over T+OFS (n=2344). 12-yr DFS was 80.5% vs. 75.9% (4.6% absolute improvement; HR 0.79 95% CI 0.70-0.90), 12-yr BCFI was improved by 4.1% and 12-yr DRFI by 1.8%. At 12 years OS was excellent in both groups, 90.1% in pts assigned E+OFS vs 89.1% in pts assigned T+OFS (HR 0.93; 95% CI, 0.78-1.11). There was heterogeneity of relative treatment effect according to HER2 status. When enrollment commenced, anti-HER2 adjuvant therapy was not standard; 53% of 583 pts with HER2+ tumors received HER2-targeted therapy. Below are Kaplan-Meier 12-yr estimates for patients with HER2 negative tumors by trial and chemotherapy stratum and for those with high-grade tumours, as an example of high-risk feature (Table). There is an emerging OS benefit for E+OFS vs T+OFS in pts with HER2 negative tumors who received chemotherapy in both trials.In pts with HER2-negative tumors, clinically-relevant outcome benefits were also seen in other high-risk subgroups: 12-yr DFS and OS were improved by 7.4% and 2.7%, respectively, in pts with pN1a disease, and by 10.6% and 4.5%, respectively, in those with tumors & gt;2cm. Conclusions After 13 years MFU, adjuvant E+OFS, as compared with T+OFS, shows a sustained reduction in the risk of recurrence, more consistent in HER2 negative patients and in those with high-risk disease features, e.g., indication for adjuvant chemotherapy and G3 tumors. Oncologists may use this information to discuss potential benefits of E+OFS with individual patients. Follow-up continues for 5 additional years. Chemotherapy HER2-negativeSOFTT+OFS (n=424)E+OFS (n=411)Absolute difference12-yr DFS67.4%74.1%6.7%12-yr OS81.1%84.4%3.3%TEXTT+OFS (n=656)E+OFS (n=661)Absolute difference12-yr DFS71.0%78.4%7.4%12-yr OS83.5%86.8%3.3%No chemotherapy HER2-negativeSOFTT+OFS (n=445)E+OFS (n=447)Absolute difference12-yr DFS82.9%88.2%5.3%12-yr OS96.1%96.9%0.9%TEXTT+OFS (n=499)E+OFS (n=492)Absolute difference12-yr DFS80.2%86.7%6.5%12-yr OS95.9%96.2%0.2%G3 HER2-negativeT+OFS (n=423)E+OFS (n=405)Absolute difference12-yr DFS62.7%73.0%10.3%12-yr OS78.1%83.6%5.5% Citation Format: Meredith M Regan, Barbara A Walley, Gini F Fleming, Prudence A Francis, Marco A Colleoni, István Láng, Henry L Gómez, Carlo A Tondini, Harold J Burstein, Matthew P Goetz, Eva M Ciruelos, Vered Stearns, Hervé R Bonnefoi, Silvana Martino, Charles E Geyer, Jr, Claudio Chini, Alessandro M Minisini, Simon Spazzapan, Thomas Ruhstaller, Eric P Winer, Barbara Ruepp, Sherene Loi, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials [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 GS2-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-12-01-P5-12-01
    Abstract: Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. We hypothesized that the rise in estrogen levels during short treatment interruptions would resensitize breast cancer cells to letrozole and improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). We previously reported the primary endpoint after 60 mos median follow-up: extended intermittent letrozole did not improve DFS vs extended continuous letrozole. However, only 9% of pts had breast cancer events, justifying updating the analysis with longer follow-up. The dynamic of recovery of estrogen levels after stopping letrozole therapy has not been previously reported. Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomized to an additional 5 yrs continuous letrozole (2.5 mg daily; n=2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n=2443). We report the final analysis of the SOLE trial after 84 mos median follow-up. In SOLE-EST, levels of estradiol (E2), estrone (E1) and estrone sulphate (E1S) at 0, 9, 10.5 and 12 mos after randomization were determined using a highly sensitive assay in a subgroup of 90 evaluable patients (21 in the continuous and 69 in the intermittent group). Results: There were 923 DFS events. 7 yr DFS was 81.5% in both groups. More pts had distant metastases in the continuous group (8.7% vs 7.5%) while second (non-breast) malignancies were more frequent in the intermittent group (5.5% vs 4.7%). Similar outcomes were observed for breast cancer-free interval (BCFI) (88.6% vs 88.0%), distant recurrence-free interval (DRFI) (91.6% vs 90.4%), and overall survival (OS) (90.6% vs 89.6%) for pts assigned intermittent vs continuous letrozole. In the intermittent group, median E2, E1 and E1S levels more than doubled compared with levels at 9 mos after randomization in the first 6 weeks after stopping letrozole during the treatment free interval while levels were stable for the 21 pts tested in the continuous group. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. Similar outcome was consistently observed for BCFI, DRFI and OS. The SOLE-EST substudy indicates an important increase in estrogen levels as soon as 6 weeks after stopping letrozole therapy in the intermittent group. Further investigation of prior exposure to aromatase inhibitors in relation with outcome and with E2, E1 and E1S levels in SOLE-EST are underway. Citation Format: Guy Jerusalem, Subrina Farah, Jacquie Chirgwin, Stefan Aebi, Per Karlsson, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Seamus O'Reilly, Andrea Gombos, Thomas Ruhstaller, Harold Burstein, Manuela Rabaglio, Barbara Ruepp, Giuseppe Viale, Richard D Gelber, Alan S Coates, Angelo Di Leo, Aron Goldhirsch, Meredith Regan, Marco Colleoni. SOLE (study of letrozole extension), a phase 3 randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC): Final analysis and sole estrogen substudy (SOLE-EST) [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 P5-12-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD9-01-PD9-01
    Abstract: Background: The AJCC 8th edition pathologic prognostic staging (PPS) system, which incorporates both anatomic and biologic factors, was developed using data from patients captured in the National Cancer Database diagnosed 2010-2012 in whom complete anatomic (T, N and M category) as well as biologic data (grade, ER, PR, HER2) were available. The clinical endpoint was 3-year overall survival. In addition, the use of genomic assays was incorporated based on the initial report from the TAILORx trial, with patients with T1-2N0 hormone-receptor positive, HER2 negative (HR+,HER2-) breast cancer and an Oncotype DX Recurrence Score® (RS) result & lt;11 being staged as PPS IA. Given availability of long-term prospective followup data from TAILORx, we undertook this study to examine if the RS criteria for downstaging to PPS IA can be expanded using the patients enrolled on this trial. Methods: TAILORx assigned T1-2N0 HR+HER2- breast cancer patients with RS & lt;11 to endocrine therapy (ET) alone and RS & gt;25 to chemotherapy followed by ET (CET). Those with RS 11-25 were randomized to ET or CET. 10,273 patients were enrolled. Patients with incomplete HR status or grade and those with T3 disease were excluded for this analysis. Recurrence-free survival (RFS) in patients with RS & lt;11 were compared between patients that did and did not fall into current AJCC PPS IA category using the Kaplan-Meier method. Results: 9,535 patients were included for analysis. The majority were & gt; 50 years old (n=6893, 72.3%), had T1 tumors (n=6561, 68.8%), grade 2 disease (n=5291, 55.5%), and underwent lumpectomy (n=6855, 71.9%). RS breakdown was & lt;11 in 1539 (16.1%), 11-17 in 3423 (35.9%), 18-25 in 3088 (32.4%) and & gt;25 in 1485 (15.6%). 8,698 (91.2%) patients were AJCC PPS IA (including all T1N0 patients regardless of RS), and 837 (8.8%) were not PPS IA. Median follow-up time was 95 months. PPS IA patients had 8-yr RFS of 94.2% which was statistically similar to patients with RS 11-17 that were not PPS IA (91.7%, p=0.07) and better than patients with RS & gt;18 that were not PPS IA (85.4% for RS 18-25, 76.0% for RS & gt;25, p & lt;0.01). For patients with a RS 11-17 that were not PPS IA receiving ET alone, 8-yr RFS was 93.3% which was statistically similar to PPS IA patients receiving ET alone (94.9%, p=0.24). There was no RFS benefit with CET for patients with RS 11-17 not PPS IA (Table). Conclusions: Patients with T1-2N0 HR+HER2- breast cancer and RS & lt;18 have similar RFS to patients staged as PPS IA by the current AJCC staging system, regardless of treatment, suggesting that consideration could be given to expanding the criteria for pathologic prognostic stage IA to include RS & lt;18. Comparison of RFS in patients with Stage IA and not Stage IA by AJCC PPS, n=9535Stage IANot stage IA, RS 11-17Not stage IA, RS 18-25Not stage IA, RS & gt;25All Patients, n=9535n=8698n=169n=269n=3998yr RFS % (95% CI)94.2 (93.6-94.8)91.7 (87.0-96.4)85.4 (80.3-90.5)76.0 (69.1-82.9)P-value*Ref0.07 & lt;0.01 & lt;0.01ET, n=5370n=5123n=88n=135n=248yr RFS % (95% CI)94.9 (94.1-95.7)93.3 (87.6-99.9)85.1 (77.8-92.4)58.3 (77.8-92.4)P-value*Ref0.24 & lt;0.01 & lt;0.01CET, n=4165n=3575n=81n=134n=3758yr RFS % (95% CI)93.2 (92.2-94.2)90.0 (82.4-97.6)85.8 (78.7-92.9)76.9 (69.8-84.0)P-value*Ref0.019 & lt;0.01 & lt;0.01ET endocrine therapy; CET chemoendocrine therapy*compared to T1-2N0 patients with PPS IA Citation Format: Olga Kantor, Harold J Burstein, Tari King, Steven Shak, Christy Russell, Armando E Giuliano, Gabriel N Hortobagyi, Eric P Winer, Larissa A Korde, Joseph A Sparano, Elizabeth A Mittendorf. Expanding downstaging criteria in AJCC pathologic prognostic staging using OncotypeDx Recurrence Score® assay in T1-2N0 hormone-receptor positive patients enrolled in the TAILORx trial [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 PD9-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS3-06-GS3-06
    Abstract: Background CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have a well-established role in the management of hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). The benefit of continuing CDK4/6i beyond progression in combination with a different ET has not been confirmed. Preclinical data suggest synergy between CDK4/6i and PD-L1 inhibition. The PACE trial prospectively evaluates whether continuation of the CKD4/6i palbociclib beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in ET to fulvestrant, improves outcomes beyond change to fulvestrant alone, as well as explores the activity of the palbociclib, fulvestrant, and avelumab triplet. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial, open at 11 U.S. sites. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after & gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to fulvestrant alone (F); fulvestrant and palbociclib (F+P); or fulvestrant, palbociclib, avelumab (F+P+A), with tumor assessments every 8 weeks. Blood for circulating tumor DNA (ctDNA) analysis was collected at baseline, at times of tumor assessments, and at progression. The primary objective was to evaluate progression-free survival (PFS) with F+P vs F; secondary objectives included PFS with F+P+A vs F, objective response rate (ORR) in all arms, and safety. A sample size of 220 patients was planned to provide 80% power to detect an improvement in PFS with HR 0.6154 with F+P vs F (6.5 vs 4 mo; α(1)=0.05). Results A total of 220 pts were randomized from 9/2017-2/2022 (F: n=55, F+P: n=111, F+P+A: n=54); median age 57 years (range 25-83), 85% non-Hispanic (7.7% non-Hispanic black), 8.6% Hispanic, 6.4% unknown. 40% had de novo MBC, 60% had visceral disease, and 14% bone-only disease. 16% had 1 prior line of chemotherapy for MBC, 90% had received prior palbociclib, 4.5% ribociclib, 4.1% abemaciclib, 1.4% palbociclib and ribociclib. Pts entered the trial after a median 19 mo of prior CDK4/6i plus AI (interquartile range 12-31 mo). A total of 10 (5%) pts received protocol therapy as first line ET for MBC, 169 (77%) as second line, and 41 (17%) as beyond second line. 88% entered the trial directly after progression on CDK4/6i. After a median follow-up of 24 mo, 18 pts remained on protocol treatment. PFS was not improved with F+P vs F (median 4.6 vs 4.8 mo; HR=1.11, 90% CI 0.79-1.55; 2-sided p=0.62). Median PFS was 8.1 mo with F+P+A (HR=0.75 vs F, 90% CI 0.50-1.12; 2-sided p=0.23). ORR was 7.3% (90%CI 1.5-13.0) with F, 9.0% F+P (4.5-13.5%) and 13.0% F+P+A (5.4-20.5%). No new safety signals have been observed. Analysis of ctDNA panel sequencing encompassing 70 genes from 184 baseline samples, including correlation with known and hypothesized resistance genes, will be presented. Conclusions For ER+/HER2- breast cancer, combining palbociclib with fulvestrant beyond progression on prior CDK4/6i and AI did not significantly improve PFS compared with using fulvestrant alone. The observed longer PFS when a PD-L1 inhibitor was added to fulvestrant plus palbociclib is an intriguing signal in this ER+ population. Translational studies of blood and tumor tissue are ongoing and will be presented. Citation Format: Erica L. Mayer, Yue Ren, Nikhil Wagle, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy D. Miller, Trevor Jolly, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Natalie Sinclair, Meredith Faggen, Caroline Block, Naomi Ko, Ann Partridge, Wendy Y. Chen, Michelle K. DeMeo, Victoria Attaya, Amanda Okpoebo, Yuan Liu, Eric Gauthier, Harold Burstein, Meredith Regan, Sara Tolaney. GS3-06 Palbociclib After CDK4/6i and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic 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 GS3-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. GS1-05-GS1-05
    Abstract: Background: The APT trial previously demonstrated that adjuvant TH is associated with favorable outcomes in patients (pts) with small HER2-positive BC. The ATEMPT trial sought to determine if adjuvant T-DM1 is associated with less toxicity than TH, and if it is associated with a clinically acceptable disease-free-survival (DFS) in pts with Stage I HER2+ BC. Methods: ATEMPT is an investigator-initiated, randomized, multicenter, phase II adjuvant study of T-DM1 vs TH. Pts with Stage I centrally confirmed HER2+ BC (IHC 3 + and/or FISH & gt; 2.0) were eligible. Pts were randomized 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks (w) for 17 cycles or T 80 mg/m2 IV with H qw x 12w (4 mg/kg load →2 mg/kg), followed by H x 39w (6 mg/kg q 3w). The co-primary endpoints were to compare the incidence of clinically relevant toxicities (CRT) in pts treated with T-DM1 vs TH and to evaluate the DFS in pts receiving T-DM1. CRT included grade ≥3 non-hematologic toxicity, grade ≥2 neurotoxicity, grade ≥4 hematologic toxicity, febrile neutropenia, and any toxicity requiring dose delay or discontinuation of protocol therapy. DFS events included invasive local, regional or distant recurrence, contralateral invasive breast cancer or death from any cause. With 375 and 125 pts randomized to T-DM1 and TH, respectively, there was 81% power to detect a 40% relative reduction in CRT between T-DM1 and TH. An interim analysis for comparison of CRT was performed when two-thirds of pts had completed therapy. For evaluation of DFS, the study was sized to have 95% power to distinguish between 3-year failure rates of 9% vs. 5% based on the total patient-years of follow-up (PYFU). Planned interim analyses were designed to stop early for futility at 186, 486, 861, and 1236 PYFU, and T-DM1 would be deemed worthy of further study with & lt;39 DFS events after 1600 PYFU. All pts who began protocol therapy were included in the analyses. Results: 512 pts with HER2+ tumors were enrolled and 497 began protocol therapy (383 T-DM1, 114 TH). 73% had hormone-receptor positive tumors. 11% of tumors were T1a; 31% T1b; 57% T1c. After interim analyses and continued review of safety, the Data Safety Monitoring Board approved release of study results. CRT were experienced by 25% of pts receiving T-DM1 and 36% of patients receiving TH; the difference was statistically significant (p=.03) but the relative reduction was & lt; 40% (p=0.95). 2% (9/383) of pts receiving T-DM1 experienced g3/4 neurotoxicity compared to 7% (8/114) of pts receiving TH; 17% of pts discontinued T-DM1 early due to adverse events. With 1562 PYFU and a median follow-up of 3.0 years, a total of 11 DFS events in the T-DM1 arm (1 distant recurrence, 3 local recurrences, 3 contralateral breast cancers, 1 death due to recurrent breast cancer, 3 deaths from other causes) and 6 events in the TH arm (2 distant recurrences, 3 local recurrences, and 1 contralateral breast cancer) have occurred. The 3 yr DFS for pts receiving T-DM1 was 97.5% (95% CI:95.9%-99.3%) and for TH was 93.2% (95%CI: 88.1%-98.7%). Conclusion: This represents the first report of pts receiving T-DM1 monotherapy as adjuvant treatment for Stage I HER2+ BC. The regimen was associated with very few recurrences in the study population. T-DM1 was associated with significantly fewer CRT than TH, but did not meet the preplanned 40% relative reduction in toxicity. Updated efficacy data will be presented. Citation Format: Sara M Tolaney, Lorenzo Trippa, William Barry, Jiani Hu, 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 K. Gadi, Michael Constantine, Kit Cheng, Frederick Briccetti, Bryan Schneider, Merrill Garrett, Kelly Marcom, Kathy Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel Jankowitz, Michelle Demeo, Ann Partridge, Harold Burstein, Eric P. Winer, Ian Krop. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. PD10-02-PD10-02
    Abstract: 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 & lt;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 & lt;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 & lt;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.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. S3-08-S3-08
    Abstract: Background It is uncertain if the addition of OFS to adjuvant endocrine therapy with T improves outcomes in premenopausal HR+ BC. The SOFT trial was designed to determine the value of OFS in women who remain premenopausal and are treated with T (OFS question) and also to test whether an AI improves outcome in premenopausal women with HR+ BC treated with OFS (AI question). In the combined analysis of the TEXT and SOFT trials (AI question), the group treated with the AI exemestane+OFS had a significantly better disease-free survival (DFS) than those with T+OFS. This abstract presents the results of the OFS question (n=2,045). Patients and Methods Between November 2003 and January 2011, the SOFT phase 3 trial randomized 3066 premenopausal women with HR+ BC to 5 years of adjuvant endocrine therapy with exemestane+OFS versus T+OFS versus T alone, with OFS initiated by choice of GnRH agonist triptorelin, oophorectomy or ovarian irradiation. Prior chemotherapy was allowed, provided women had confirmed premenopausal estradiol levels within 8 months of completing chemotherapy. The primary end point was DFS which included invasive local, regional, distant and contralateral breast events, second non-breast malignancies and deaths without prior cancer. Because of a lower-than expected overall event rate and to ensure results within a reasonable time-frame, a protocol amendment in 2011 changed the originally event-driven analysis plan. The amendment (1) designated the comparison of T+OFS versus T alone as the primary analysis for SOFT (n=2045), recognizing that the statistical power for the original three pairwise comparisons would be substantially reduced and (2) specified that the primary analysis of T+OFS versus T be undertaken when median follow-up was at least 5 years. The comparison would be tested at the 2-sided 0.05 level with no interim analysis. Based on the projected number of events at the lower rates, the estimated power to detect hazard ratios of 0.75, 0.70, and 0.66 for the comparison would be 52%, 69%, and 80%. Results The SOFT trial completed planned patient enrollment with an international collaboration involving 426 centres from BIG and NABCG led by the International Breast Cancer Study Group (IBCSG). Numbers of patients randomized, randomization strata, and pt age are summarized in the Table. The database lock for the primary analysis of the OFS question will occur in September 2014 and the final analysis will be completed by October 15, 2014. SOFT Patients (%)Tamoxifen alone1021 (33%)Tamoxifen+OFS1024 (33%)Exemestane+OFS1021 (33%)*  Prior Chemotherapy54%Lymph node positive35%Median age (% & lt; 40 years)43 years (30%)*Patients randomized to Exemestane+OFS are not part of the current analysis Conclusions We will present the primary analysis of outcomes and toxicities by treatment for women randomized to receive T+OFS versus T and address the value of OFS in addition to T as adjuvant endocrine therapy for premenopausal women with HR+ BC. Citation Format: Aron Goldhirsch, Richard D Gelber, Prudence A Francis, Meredith M Regan, Gini F Fleming, Istvan Lang, Eva M Ciruelos, Meritxell Bellet, Herve Bonnefoi, Miguel A Climent, Lorenzo Pavesi, Harold J Burstein, Silvana Martino, Nancy E Davidson, Charles E Geyer Jr, Barbara A Walley, Robert E Coleman, Pierre Kerbrat, Manuela Rabaglio-Poretti, Alan S Coates. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Analysis of the SOFT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 4 ( 2007-02-15), p. 1198-1207
    Abstract: Purpose: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)–positive breast cancer. Experimental Design: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. Results: Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T1 tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T4 stage (P = 0.02) and express basal markers (P & lt; 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001). Conclusions: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-13-02-P2-13-02
    Abstract: 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 & lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% 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.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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