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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P2-14-08-P2-14-08
    Abstract: Introduction: Even though randomized controlled trials could not show a significant survival benefit for the use of neoadjuvant systemic therapy (NST), it is increasingly recommended for patients with clinically node-positive breast cancer due to its implications on prognosis, locoregional downstaging and response-driven adjuvant systemic therapy. The aim of this study was to assess the need for international standardization of treatment recommendations by evaluating clinical practice heterogeneity in use of NST for patients with clinically node-positive breast cancer in Europe. Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) after randomization of the first 500 patients with clinically node-positive breast cancer who underwent axillary lymph node dissection (ALND) or axillary radiation (ART) without ALND after tailored axillary surgery (TAS) in the context of extended regional nodal irradiation. Clinically node-positive breast cancer was defined by confirmed nodal disease at the time of initial diagnosis; in case of neoadjuvant therapy, residual nodal disease was mandatory. Investigators were encouraged to enroll all eligible patients consecutively. However, TAXIS is unique inasmuch as its pragmatic design allows both the neoadjuvant and adjuvant setting according to the preferences of the treating physicians and institutions and thus provides an excellent opportunity to study patterns and trends in use of NST in patients with clinically positive nodes in Europe. Results: A total of 500 patients with a median age of 57 years (IQR: 48-69 years) were included at 44 breast centers in 6 European countries from August 2018 to June 2022. Subtype was hormone receptor (HR) positive (+) and human epidermal growth factor receptor 2 (HER2) negative (-) in 393 (80.0%), HR+/HER2+ in 52 (10.6%), HR-/HER2+ in 5 (1.0%) and HR-/HER2- in 34 (6.9%) patients. The rate of patients undergoing NST was 31.4% with a significant upward trend over time during the study period (from 20.0% in 2018 to 38.1% in 2022; p=0.044). The use of NST varied significantly by country (p= & lt; 0.001) and by site (p=0.015). For patients with clinical AJCC tumor stage II and III, the rates of patients undergoing NST in Switzerland were 26.5% (18 of 68) and 35.9% (92 of 256), in Germany 22.2% (2 of 9) and 30.4% (7 of 23), in Austria 50% (7 of 14) and 60% (9 of 15) and in Hungary 0% (0 of 15) and 20.7% (18 of 87), respectively (p=0.019 and 0.004). Large differences by country were found for ER+/HER2- breast cancer, ranging from 13.1% (11 of 84) in Hungary to 47.8% (11 of 23) in Austria (p=0.007). Within Switzerland, which was the country with most included patients (328 of 500) and participating sites (n=25), the rate of patients undergoing NST for ER+/HER2- breast cancer varied considerably by site, ranging from 10% (2 of 20) to 50% (11 of 22). Discussion: This study revealed substantial heterogeneity in clinical practice in Europe, indicating the need for development of and adherence to consistent guidelines to standardize the international use of NST. Citation Format: Walter P. Weber, Zoltan Matrai, Stefanie Hayoz, Guido Henke, Daniel R. Zwahlen, Günther Gruber, Frank Zimmermann, Thomas Ruhstaller, Simone Muenst, Markus Ackerknecht, Christian Kurzeder, Sherko Küemmel, Vesna Bjelic-Radisic, Viktor Smanykó, Conny Vrieling, Rok Satler, Inna Meyer, Charles Becciolini, Susanne Bucher, Colin Simonson, Peter M. Fehr, Natalie Gabriel, Robert Maráz, Dimitri Sarlos, Konstantin J. Dedes, Cornelia Leo, Gilles Berclaz, Hisham Fansa, Christopher Hager, Klaus Reisenberger, Ákos Sávolt, Christian F. Singer, Roland Reitsamer, Jelena Winkler, Giang Thanh Lam Lam, Mathias K. Fehr, Tatiana Naydina, Magdalena Kohlik, Karine Clerc, Valerijus Ostapenko, Florian Fitzal, Martin Heidinger, Nadia Maggi, Alexandra Schulz, Pagona Markellou, Loïc Lelièvre, Daniel Egle, Jörg Heil, Michael Knauer, Christoph Tausch. Trends in neoadjuvant systemic therapy rates in Europe: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-08.
    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. 83, No. 5_Supplement ( 2023-03-01), p. PD3-01-PD3-01
    Abstract: Background: The phase 3 KEYNOTE-522 study (NCT03036488) showed that pembrolizumab (pembro) administered in combination with neoadjuvant chemotherapy (chemo) and then continued as adjuvant monotherapy resulted in statistically significant and clinically meaningful improvements in pathological complete response (pCR) and event-free survival (EFS) in patients with early triple-negative breast cancer (TNBC). In this post hoc analysis, we assessed outcomes by patterns of adjuvant radiation therapy (RT) administration. Methods: Patients with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2:1 to pembro 200 mg Q3W or placebo, both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, patients received pembro or placebo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Dual primary endpoints are pCR, defined as ypT0/Tis ypN0, and EFS. EFS and adverse events (AEs) that occurred during the adjuvant phase were examined in patient subgroups defined by receipt of adjuvant RT (yes or no) and the pattern of adjuvant RT and pembro administration, either concurrent (the last adjuvant RT exposure was after the first dose of adjuvant pembro or placebo) or sequential (the last adjuvant RT exposure was before the first dose of adjuvant pembro or placebo). Results: Among 1174 randomized patients, 715 (60.9%) received adjuvant RT (n=454 pembro; n=261 placebo) and 459 (39.1%) did not (n=330 pembro; n=129 placebo). At data cutoff (March 23, 2021), median follow-up was similar (~38 months) in both subgroups. EFS was longer in the pembro arm compared to the placebo arm in patients who received adjuvant RT (either concurrently or sequentially) and those who did not (Table). Grade 3-5 treatment-related AE rates for pembro vs placebo were 5.9% vs 2.7% with adjuvant RT (4.9% vs 2.2% with concurrent RT; 6.8% vs 3.1% with sequential RT) and 7.5% vs 2.9% without adjuvant RT. Treatment-related AEs led to death in 2 patients (0.4%); both occurred in the pembro arm in patients who received adjuvant RT. Immune-mediated AE rates were 10.6% vs 5.0% with adjuvant RT (9.7% vs 4.4% with concurrent RT; 11.8% vs 5.7% with sequential RT) and 9.0% vs 10.0% without adjuvant RT in the two treatment arms, respectively. Conclusion: In this post hoc analysis, the addition of pembro to neoadjuvant chemo followed by adjuvant pembro provided a clinically meaningful EFS benefit, independent of adjuvant RT administration. An EFS benefit was observed in patients who received pembro with either concurrent or sequential adjuvant RT. The addition of pembro to adjuvant RT was generally well tolerated. Similar rates of treatment-related AEs and immune-mediated AEs were seen in patients who received adjuvant RT and pembro either concurrently or sequentially, although the sample sizes are modest. These results are consistent with the therapeutic benefit seen with neoadjuvant pembro plus chemo followed by adjuvant pembro in the intention-to-treat population of patients with early TNBC randomized in KEYNOTE-522. Table: EFS by Adjuvant RT in KEYNOTE-522 Citation Format: Heather McArthur, Javier Cortés, Rebecca Dent, Joyce O’Shaughnessy, Lajos Pusztai, Sherko Küemmel, Theodoros Foukakis, Yeon Hee Park, Rina Hui, Nadia Harbeck, Masato Takahashi, Michael Untch, Peter A. Fasching, Fatima Cardoso, Carsten Denkert, Yalin Zhu, Yu Ding, Wilbur Pan, Peter Schmid. Neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy followed by adjuvant pembrolizumab vs placebo for early TNBC: Post hoc analysis of adjuvant radiation therapy in the phase 3 KEYNOTE-522 study [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 PD3-01.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. OT1-03-06-OT1-03-06
    Abstract: Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (LV) is an investigational antibody-drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to approximately 4 molecules of monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score & lt; 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 every 21 days plus pembrolizumab 200 mg on Day 1 q3w. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress) [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 OT1-03-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS4-02-GS4-02
    Abstract: Background: Data on the oncologic safety of omission of axillary lymph node dissection (ALND) in node positive (N+) patients who downstage to ypN0 with neoadjuvant chemotherapy (NAC) is sparse. Additionally, there is no consensus on which axillary staging procedure should be used in this setting, sentinel lymph node biopsy (SLNB) alone or in combination with localization and retrieval of the clipped positive node, also known as targeted axillary dissection (TAD). Whether the reduction in the false negative rate observed with TAD translates into a significant reduction in the rate of axillary recurrence is unknown. We sought to evaluate oncologic outcomes after omission of ALND in a large, real-world cohort of breast cancer (BC) patients and to compare rates of axillary recurrence after SLNB with dual tracer mapping vs. TAD. Methods: Data were collected from 19 centers in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks. Patients with T1-4 biopsy-proven N1-3 BC who underwent NAC followed by axillary staging with either SLNB with dual tracer mapping or TAD and who were pathologically node negative (ypN0) were included. ypN0 was defined as the absence of any tumor or isolated tumor cells. Competing risk analysis was performed to assess the cumulative incidence rates of axillary recurrence, locoregional recurrence, and any invasive (locoregional or distant) recurrence. Two-year cumulative incidence rates were compared between TAD and SLNB using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 785 patients (565 treated with SLNB and 220 with TAD) treated with NAC followed by surgery from 01/2014-12/2020. Median patient age was 50 years. The majority (57%) of patients had clinical T2 tumors, and 95% had N1 disease. Most (55%) were HER2+, and 21% were triple negative. Most patients (81%) received anthracycline and taxane-based chemotherapy regimens, but NAC regimens differed between patients treated with TAD and those treated with SLNB (Table 1). All patients with HER2+ tumors received anti HER2 therapy. Nodal radiotherapy was administered to 76% of patients, and was more common in patients who underwent TAD (82% TAD vs 74% SLNB, p=0.017). Breast pathologic complete response (ypT0/is) was more frequent among those patients that had TAD (80% TAD vs. 66% SLNB, p & lt; 0.001). TAD localization was with wire in 46%, radioactive seed in 40%, ultrasound in 5%, tattoo in 2%, and with a combination of these techniques in 7%. The clipped node was successfully retrieved in 94% of TAD cases. The median number of lymph nodes removed was lower in the TAD group compared to the SLNB group [3 (IQR 3-5) vs 4 IQR 3-5), p & lt; 0.001], as was the median number of sentinel lymph nodes [3 (IQR 2-4) vs 4 IQR 3-5), p & lt; 0.001] (Table 1). The 5-year rates of any axillary recurrence, locoregional recurrence, and any invasive recurrence in the entire cohort were 1.1% (95%CI 0.39-2.4%), 3.1% (95%CI 1.6-5.3%) and 10% (95%CI 7.6-13%), respectively. The two-year cumulative incidence of axillary recurrence did not differ between patients treated with TAD compared to SLNB (0% vs 0.9%, p=0.19). Conclusion: Early axillary recurrence after omission of ALND in patients who successfully downstage from N+ to ypN0 with NAC is a rare event following both SLNB or TAD, and was not significantly lower in TAD than SLNB. Although longer follow-up is needed to confirm these findings, the main advantage of TAD seems to be a reduction in the number of lymph nodes removed. Overall, these results support omission of ALND in patients who successfully downstage to node negative disease after NAC. Table 1: Clinicopathological Features of the Study Cohort, Stratified by Axillary Staging Technique Citation Format: Giacomo Montagna, Mary Mrdutt, Astrid Botty, Andrea V. Barrio, Varadan Sevilimedu, Judy C. Boughey, Tanya L. Hoskin, Laura H. Rosenberger, E Shelley Hwang, Abigail Ingham, Bärbel Papassotiropoulos, Bich Doan Nguyen-Sträuli, Christian Kurzeder, Danilo Diaz Aybar, Denise Vorburger, Dieter Michael Matlac, Edvin Ostapenko, Fabian Riedel, Florian Fitzal, Francesco Meani, Franziska Fick, Jacqueline Sagasser, Jörg Heil, Konstantin J. Dedes, Laszlo Romics, Maggie Banys-Paluchowski, Maria Del Rosario Cueva Perez, Marcelo Chavez Diaz, Martin Heidinger, Mathias K. Fehr, Mattea Reinisch, Nadia Maggi, Nicola Rocco, Nina Ditsch, Oreste Davide Gentilini, Regis Resende Paulinelli, Sebastian Sole Zarhi, Sherko Küemmel, Simona Bruzas, Simona Di Lascio, Tamara Parissenti, Uwe Güth, Valentina Ovalle, Christoph Tausch, Monica Morrow, Thorsten Kühn, Walter P. Weber. Oncological Outcomes Following Omission of Axillary Lymph Node Dissection in Node Positive Patients Downstaging To Node Negative with Neoadjuvant Chemotherapy: the OPBC-04/EUBREAST-06/OMA study [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 GS4-02.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-05-36-P1-05-36
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-05-36-P1-05-36
    Abstract: Introduction: Long QT syndrome is a common cardiotoxic side effect of various anti-tumor drugs. Previous cardiological monitoring of oncological patients is primarily complex and requires for non-internal oncologists a consultation. Therefore, the QTc-Tracker smartphone APP was developed, which enabled a tele-cardiological diagnosis of the QTc time with standard single-lead ECG devices. As a result, diagnosis times could already be reduced by 99%. The further development examined an automatic determination of the QT time using the smartphone APP. However, since single-lead ECG devices are significantly more susceptible to interference, the determination of the QT time is more complex than with 12-lead ECGs. Methods: The QTc-Tracker smartphone APP was developed to determine the QT time. Self-tracker single-lead ECG devices were used to record the lead I signal. The ECG recordings were analyzed in the APP and passed on to an external cardiologist as reference. The APP used artificial intelligence and was trained in the first phase and validated in the second phase. The first phase aimed to improve QT time detection. The results of the APP were compared with the findings of the external cardiologist. In both phases, ECGs from breast cancer patients receiving ribociclib were used. Results: A total of 1889 single-lead ECGs were carried out. 248 of these could not be evaluated (13%). QTc prolongation, according to CTCAE, was diagnosed in 41 cases (2.5%). 878 of the evaluable ECGs were used for the training phase and 763 for the evaluation phase. In the first group (before the improvement), the sensitivity to automatically detect a prolongation of the QT time was 36%, and the specificity was 96%. In the evaluation collective (after the training), the sensitivity went up to 85%, and the specificity was unchanged at 96%. Conclusions: The trained method of the QTc tracker is able to reliably detect a QT time lengthening even without a cardiological diagnosis only by using single-lead self-tracker ECG’s. In the rare cases in which an elongation was not detected, the cardiac diagnosis was only a few milliseconds above the threshold value. This artificial intelligence-based smartphone APP is not intended to replace the cardiological diagnosis, but it can simplify routine processes and help to decide which patients need a cardiological examination more urgently. Citation Format: Timo Schinköthe, Christian Horst Tonk, Nadia Harbeck, Vanda Carmelo, Joana Gomes Feliciano, Rachel Wuerstlein, Sherko Küemmel, Annette Schmidt. AI-Based Smartphone App Using a Single-Lead ECG for Automated QTc Diagnostics in Oncology [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 P1-05-36.
    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. 83, No. 5_Supplement ( 2023-03-01), p. PD17-12-PD17-12
    Abstract: Background: In the Phase III MONALEESA (ML)-2, -3 and -7 trials, a 600 mg dose of ribociclib (RIB) demonstrated significant overall survival benefit in patients (pts) with HR+/HER2− advanced breast cancer (ABC) but was associated with QTcF ( & gt;480 ms, 3%-7%) and neutropenia (G3/4, 57%-64%) adverse events (AEs) which were managed by dose reductions. The Phase II AMALEE study was performed as a postmarketing commitment to assess whether reducing the starting dose of RIB from the recommended dose (3 wk on, 1 wk off) of 600 mg/day to 400 mg/day decreases QTcF prolongation without compromising the efficacy of first-line RIB in pts with HR+/HER2− ABC. Here, we present efficacy and safety results from the primary analysis of AMALEE. Methods: AMALEE is a randomized Phase II open-label study including pre- and postmenopausal pts with HR+/HER2− ABC with no prior therapy for ABC. Pts received RIB 400 mg + nonsteroidal aromatase inhibitor (NSAI) or RIB 600 mg + NSAI. The primary endpoint is to determine whether overall response rate (ORR) in the 400 mg arm is noninferior to the 600 mg arm. The key secondary endpoint is QTcF prolongation at cycle 1, day 15 (C1D15) 2 hours post dose. Additional endpoints included safety, progression-free survival (PFS), duration of response (DOR), time to response (TTR), and pharmacokinetics. Results: A total of 376 pts were randomized 1:1 to receive RIB at either 400 mg or 600 mg doses. Baseline (BL) characteristics and prior antineoplastic therapy were balanced across treatment (tx) arms. At the time of the data cutoff (June 11, 2021), median follow-up was 14.9 mo (min, 6.1; max, 23.8), and all pts had been treated for ≥6 months from randomization or had discontinued study tx. ORR for RIB was 41.5% (95% CI, 34.4-48.7) with 400 mg vs 45.3% (95% CI, 38.1-52.6) with 600 mg (ORR ratio for RIB 400 mg vs 600 mg, 0.921 [90% CI, 0.757-1.121]). The lower 90% CI boundary did not meet the prespecified noninferiority (NI) margin of 0.814. Results for ORR by subgroups were consistent with the overall analysis set. RIB plasma exposure was lower at 400 mg than 600 mg; the geometric mean Cmax and AUC0-24h at C1D15 were approximately 28% and 43% lower in the 400 mg than the 600 mg arm (Cmax 1080 vs 1500 ng/mL and AUC0-24h 16400 vs 28600 ng × h/mL). This study met the key secondary endpoint, change in QTcF at C1D15 in the RIB 400 mg group with a 90% CI upper boundary of & lt; 20 ms. Mean change in QTcF from BL to C1D15 2 hours post dose was lower in the 400 mg (12.5 ms, 90% CI, 10.9-14.1) than the 600 mg arm (19.7 ms, 90% CI, 17.4-22.0). QTcF ≥501 ms occurred in 1.6% of pts in the 400 mg arm vs 0.5% in the 600 mg arm. Rates of G3/4 neutropenia were lower in the 400 mg (31.4%) than the 600 mg arm (46.3%). Other safety results were consistent with those previously reported for RIB in the ML trials. Median duration of exposure to RIB was 8.0 mo (min, 0.1; max, 23.7) in the 400 mg arm vs 8.8 mo (min, 0.5; max, 20.8) in the 600 mg arm. Dose reductions of RIB were more frequent in the 600 mg group with 30.5% vs 13.8% of pts requiring 1 dose reduction in the 600 mg and 400 mg groups, respectively. Dose reductions were primarily attributable to AEs, with neutropenia being the most frequently reported AE requiring a dose modification. Rates of discontinuation due to AEs were similar in the 400 mg vs 600 mg arms (8.5% vs 9.6%). PFS, DOR, and TTR data are currently immature. Conclusions: RIB at the 400 mg dose shows a better safety profile vs 600 mg in terms of key AEs that are RIB concentration dependent (neutropenia and QTcF prolongation). ORR was 3.8% lower with 400 mg than 600 mg. The lower 90% CI boundary of the ORR ratio did not meet the NI margin, thus this study was unable to demonstrate statistical NI of the 400 mg vs 600 mg dose of RIB using ORR as the endpoint. Updated results with additional follow-up and the clinically relevant endpoint PFS will be presented at the congress. Citation Format: Fatima Cardoso, William Jacot, Sherko Küemmel, Sudeep Gupta, Rama Balaraman, Liudmila Lebedeva, Yan Ji, Aparna Lakshmanan, Khalid Amin, Zheng Li, Joseph Sparano. Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced 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 PD17-12.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 26 ( 2017-09-10), p. 3046-3054
    Abstract: Human epidermal growth factor receptor 2 (HER2)–positive/hormone receptor (HR)–positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P 〈 .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported. Conclusion The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. OT3-33-01-OT3-33-01
    Abstract: Background: Aim of the OMCAT trial (‘One Million CAncer Treatment months’, NCT04531995) is improvement of cancer patient care and safety by developing artificial intelligence (AI)-based, incident prediction algorithms. Incident detection allows early notification of treatment teams, enabling timely management changes or interventions. Ultimately the algorithms can also support improved health resource allocation. This trial in progress aims to provide learning databases in breast cancer comprising both electronic patient reported outcome (ePRO) data using the mobile medical device ‘CANKADO PRO-React’ and ground truth outcome data, which provide disease-specific events of interest (“incidents”) verified by the physician (e.g., during patient examinations). Methods: Incident prediction is posed as an application of stochastic time series analysis using AI and knowledge engineering technology. The learning process begins by fitting individualized and disease-specific stochastic process models to “incident-free” intervals extracted from the ePRO data series. Incidents produce detectable deviations from “ordinary” ePRO fluctuations. The algorithms are trained on CANKADO PRO-React data to produce real-time risk functions for predicting incidents on a clinically specified time horizon. Results: Considering the heterogeneity and combinatorics of diseases, stages, therapies, and types of events considered in this study, ultimately the AI algorithms aim to discover about 360 distinct predictive relationships. The estimate of one million treatment months is derived from statistical power analysis of this target, considering estimated median documentation time of six months per patient and estimated 400-500 patients per predictive relationship. To date, 45 centers in Germany have expressed interest in participating. This participation level will enable proof of principle. Ethics votes are already available in most regions. Other centers are invited to participate in this trial. Conclusions: OMCAT opens a whole new path towards evidence-trained AI and a novel combination of patient observation and predictive care. The goals of OMCAT are ambitious and will therefore require many more supporters. Citation Format: Timo Schinköthe, Christian Horst Tonk, Ronald Kates, Sherko Küemmel, Fatima Cardoso, Nadia Harbeck, Peter Staib, Annette Schmidt. Prospective, Multi-Center, Artificial Intelligence Study for Early Prediction of Serious Events under Treatment Is Now Open for Recruitment in Breast Cancer - OMCAT Trial in Progress [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 OT3-33-01.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD15-11-PD15-11
    Abstract: Introduction: Chemotherapy is recommended for patients with luminal breast cancer and more than three positive nodes. In addition, recent landmark trials raised the question if the exact number of positive nodes is required to indicate genomic testing. In the neoadjuvant setting, response-driven therapy is increasingly used and may be influenced by surgical staging of the axilla. The present study addressed the role of axillary lymph node dissection (ALND) as decision aid for systemic therapy in a contemporary cohort of patients with clinically node-positive breast cancer in the adjuvant and neoadjuvant setting. Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614). The first 500 patients with clinically node-positive breast cancer who were randomized after tailored axillary surgery (TAS) to undergo ALND or axillary radiotherapy (ART) without ALND in the context of extended regional irradiation were included from August 2018 to June 2022. Clinically node-positive breast cancer was defined by confirmed nodal disease at the time of initial diagnosis; in case of neoadjuvant therapy, the finding of residual nodal disease was mandatory for randomization. TAS consisted of removal of palpably suspicious findings and the sentinel nodes with the option of image guidance. In the ART arm, the total number of positive nodes was not known. We analyzed the impact of ALND on rate and type of systemic therapy. Results: A total of 500 patients with a median age of 57 years (IQR: 48-69 years) were included at 44 breast centers from six European countries. Subtype was hormone receptor (HR) positive (+) and human epidermal growth factor receptor 2 (HER2) negative (-) in 393 (80.0%), HR+/HER2+ in 52 (10.6%), HR-/HER2+ in 5 (1.0%) and HR-/HER2- in 34 (6.9%) patients. Of 343 patients (68.6%) who were treated in the adjuvant setting, 297 had HR+/HER2- disease. Of these 297 patients, 145 (48.8%) underwent ART without ALND and 152 (51.2%) underwent ALND after TAS. In the ART arm, the median number of lymph nodes removed was five (IQR 4-8), three (IQR 1-4) of which were positive and in the ALND arm, the number was 19 (IQR 14-26), four (IQR 2-9) of which were positive (p & lt; 0.001). The use of ALND had no significant impact on the rate of patients with HR+/HER2- disease undergoing adjuvant chemotherapy (51.0% in the ART and 57.9% in the ALND arm, p=0.2), and there were no significant differences in type of systemic therapy with the exception of tamoxifen, which was 18.4% with ALND versus 9.0% without (p=0.018). A total of 143 patients (28.6%) underwent neoadjuvant chemotherapy, 13 had neoadjuvant antihormonal treatment and one had neoadjuvant double HER2-blockade without chemotherapy. Of the 143 patients who received neoadjuvant chemotherapy, 71 (49.7%) underwent ART without ALND and 72 (50.3%) underwent ALND. In the ART arm, the median number of lymph nodes removed was four (IQR 3-6), one (IQR 1-3) of which was positive and in the ALND arm, the number was 16 (IQR 12-19), two (IQR 1-5) of which were positive (p & lt; 0.001). The use of ALND in patients after neoadjuvant treatment had no significant impact on the rate of adjuvant systemic therapy (71.8% in the ART and 65.3% in the ALND arm, p=0.4), with no significant differences in type of chemotherapy (e.g., capecitabine: 11.3% vs 12.5%, p=0.8; T-DM1: 11.3% vs. 11.1%, p & gt;0.9) or antihormonal therapy (e.g., aromatase inhibitors: 49.3% vs. 41.7%, p=0.4; tamoxifen: 11.3% vs. 5.6%, p=0.2). Discussion: This study showed that although ALND significantly increased the number of positive nodes removed in the adjuvant and neoadjuvant setting, it had no relevant impact on rate and type of adjuvant systemic therapy. Citation Format: Walter P. Weber, Zoltan Matrai, Stefanie Hayoz, Christoph Tausch, Guido Henke, Daniel R. Zwahlen, Günther Gruber, Frank Zimmermann, Thomas Ruhstaller, Simone Muenst, Markus Ackerknecht, Sherko Küemmel, Vesna Bjelic-Radisic, Viktor Smanykó, Conny Vrieling, Rok Satler, Inna Meyer, Charles Becciolini, Susanne Bucher, Colin Simonson, Peter M. Fehr, Natalie Gabriel, Robert Maráz, Dimitri Sarlos, Konstantin J. Dedes, Cornelia Leo, Gilles Berclaz, Hisham Fansa, Christopher Hager, Klaus Reisenberger, Ákos Sávolt, Christian F. Singer, Roland Reitsamer, Jelena Winkler, Giang Thanh Lam Lam, Mathias K. Fehr, Tatiana Naydina, Magdalena Kohlik, Karine Clerc, Valerijus Ostapenko, Florian Fitzal, Martin Heidinger, Nadia Maggi, Alexandra Schulz, Pagona Markellou, Loïc Lelièvre, Daniel Egle, Jörg Heil, Michael Knauer, Christian Kurzeder. PD15-11 Axillary dissection to determine nodal burden to inform systemic therapy recommendations in patients with clinically node-positive breast cancer: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101) [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 PD15-11.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3132-3132
    Abstract: Background: The level of immune suppression in an individual breast cancer (BC) patient is relevant for having a major benefit from treatments that act via or are directed to the immune response, such as anti-HER2 agents and immune checkpoint molecules, respectively. The link(s) between the tumor immune microenvironment and treatment responses has been investigated in HER2-positive BC. This study analyzed the association between baseline expression of genes regulating T cell activities (PD1, CTLA4, LAG3, TIM3, PDL1, PDL2, FOXP3, IL10, TGFβ (1-3), FOXP1 and other related genes) and pathologic complete response (pCR) rates in the NeoALTTO trial. Methods: NeoALTTO randomized early-stage HER2-positive BC patients to neoadjuvant trastuzumab (T), lapatinib (L) or T+L for 6 weeks followed by 12 weeks of concurrent paclitaxel. Anthracyclines were given after surgery (FEC). Patients with RNA sequencing data from their baseline tumor samples (N=254 patients out of 455 from the original cohort) were included in the current study. The primary endpoint, pCR, was defined as ypT0/is ypN0. Logistic regression was used for analysis of pCR. Cox regression univariate and multivariate (adjusted for clinicopathological parameters and treatment arms) analyses were performed. Results: In the total cohort analyzed, high PD1 (odds ratio, OR: 1.4, P=0.03), PDL2 (OR: 1.4, P=0.04), CTLA4 (OR: 1.4, P=0.03) and TGFβ3 (OR: 1.4, P=0.02) expression was associated with an increased probability of achieving pCR at the multivariate analysis. ERBB2 (HER2) expression was associated with pCR in the three arms (T: OR: 2.7, P=0.02; L: OR: 2.3, P=0.01; T+L: OR: 5, P & lt;0.001). Additionally in the T+L arm, PAM50 HER2-enriched subtype (OR: 2.9, P=0.03), as well as immune genes PD1 (OR: 2.1, P=0.01), PDL1 (OR: 1.8, P=0.03) and CTLA4 (OR: 2; P=0.01), were also associated with pCR. Conclusions: In the NeoALTTO population examined, PD1, PDL2, CTLA-4 and TGFβ3 expression at diagnosis were all associated with improved pCR rates after anti-HER2 treatment. The effect of these treatments seemed to be dependent on HER2 expression levels, which was particularly relevant in the T+L arm. These observations confirm previous findings that link immune infiltrates to higher pCR rates, demonstrate the clinical significance of the PD-1 pathway and additionally show that CTLA-4 and TGFβ3 could also be important in early stage HER2-positive BC. The association of tumors linked with immune regulatory gene expression with positive responses to neoadjuvant anti-HER2 agents suggests that they act in a way that reinvigorates the antitumor immunity in the face of tumor-mediated suppression. Patients whose tumors highly express these genes may be good candidates for immunotherapy before the start or after the neoadjuvant treatment when residual disease is detected at surgery, although these hypotheses require further confirmation. Citation Format: Cinzia Solinas, Pushpamali De Silva, David Venet, Soizic Garaud, Chunyan Gu-Trantien, Florentine Hilbers, Evandro de Azambuja, Olena Werner, Lorena De la Peña, Amylou Dueck, Serena Di Cosimo, Istvan Lang, Jens Huober, Sherko Küemmel, Carsten Denkert, Roberto Salgado, Christos Sotiriou, Martine Piccart-Gebhart, Debora Fumagalli, Karen Willard-Gallo. Immune regulatory gene expression and clinical outcome in the NeoALTTO trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3132.
    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: 2019
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