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Clinical Trial
. 2023 Jun;41(3):391-401.
doi: 10.1007/s10637-023-01357-4. Epub 2023 Apr 12.

Targeting chemotherapy resistance in mesenchymal triple-negative breast cancer: a phase II trial of neoadjuvant angiogenic and mTOR inhibition with chemotherapy

Nour Abuhadra  1 , Ryan Sun  2 , Roland L Bassett Jr  2 , Lei Huo  3 , Jeffrey T Chang  4 , Mediget Teshome  5 , Alyson R Clayborn  1 , Jason B White  1 , Elizabeth E Ravenberg  1 , Beatriz E Adrada  6 , Rosalind P Candelaria  6 , Wei Yang  6 , Qingqing Ding  3 , W Fraser Symmans  3 , Banu Arun  1 , Senthil Damodaran  1 , Kimberly B Koenig  1 , Rachel M Layman  1 , Bora Lim  1 , Jennifer K Litton  1 , Alastair Thompson  5 , Naoto T Ueno  1 , Helen Piwnica-Worms  7 , Gabriel N Hortobagyi  1 , Vicente Valero  1 , Debu Tripathy  1 , Gaiane M Rauch  6 , Stacy Moulder  8 , Clinton Yam  9
Affiliations
Clinical Trial

Targeting chemotherapy resistance in mesenchymal triple-negative breast cancer: a phase II trial of neoadjuvant angiogenic and mTOR inhibition with chemotherapy

Nour Abuhadra et al. Invest New Drugs. 2023 Jun.

Abstract

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Patients and Methods:: Patients received liposomal doxorubicin (30mg/m2 intravenously [IV], every 21 days, x 4 cycles), bevacizumab (10-15mg/kg IV, every 21 days x 3 cycles), and temsirolimus (25mg IV, every 7 days, x 12 weeks) or everolimus (7.5mg orally, once daily). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden index I (RCB-I) from 5% to 20%.

Results:: From 2/11/2016 through 12/4/2019, 17 patients were enrolled. None of the study participants experienced a pCR. Among all 17 patients, 6%, 76%, and 18%, were found to have RCB-I, RCB-II, and RCB-III disease, respectively. No grade 4/5 treatment-related adverse events (TRAE) were observed. The most common grade 3 TRAEs were neutropenia (18%) and oral mucositis (18%).

Conclusion:: Neoadjuvant DAT/DAE failed to demonstrate meaningful clinical activity in patients with mesenchymal and/or metaplastic TNBC following suboptimal response to neoadjuvant AC. Further studies are needed to elucidate mechanisms of primary anthracycline resistance in metaplastic and/or mesenchymal TNBC.

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Conflict of interest statement

E.E.R. is currently employed at Eli Lilly (previously employed by MD Anderson at the time the study was conducted). W.F.S. is a co-inventor/patent of US Patent No. 11,459,617 “Targeted measure of transcriptional activity related to hormone receptors” issued on 10/4/2022 (applicant proprietor: University of Texas MD Anderson Cancer Center. Licensed to Delphi Diagnostics, Inc. and has co-founder equity from Delphi Diagnostics, Inc. R.L. has received research funding (to the institution) from Novartis and serves on the advisory board for Novartis. J.K.L. has received grant or research support from Novartis, Medivation/Pfizer, Genentech, GSK, EMD-Serono, Astra-Zeneca, Medimmune, Zenith, Jounce; participated in Speaker’s Bureau for MedLearning, Physician’s Education Resource, Prime Oncology, Medscape, Clinical Care Options; received honoraria from UpToDate; served on advisory committees or review panels for Astra-Zeneca, Ayala, Pfizer (all uncompensated), NCCN, ASCO, NIH, PDQ, SITC Breast Committee, SWOG Breast Committee. A.T. is related by marriage to an employee of Eli Lilly. D.T. has received research support (to the institution) from Novartis, Pfizer, Polyphor and has served as a consultant to AstraZeneca, Glaxosmithkline, Gilead, Oncopep, Pfizer, Novartis, AMBRX, Personalis, Sermonix, Stemline-Menarini, Puma Biotechnology. S.L.M. is currently employed by Eli Lilly (previously employed by MD Anderson at the time the study was conducted). All other authors declare that they have no relevant conflicts of interest. C.Y. has received research funding (to the institution) from Genentech, Gilead, BostonGene, Sanofi, Amgen, Pfizer, Astellas, Novartis and has served on advisory boards for Gilead. All other authors declare no relevant conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.. Study Schema.
Patients with stage I-III TNBC with mesenchymal and/or metaplastic TNBC with suboptimal responses to neoadjuvant doxorubicin and cyclophosphamide were enrolled on this study. Abbreviations: AC, Doxorubicin and Cyclophosphamide; SVR, Sonographic Volumetric Reduction. *Bevacizumab omitted for Cycle 4. Protocol amendment was to reduce the dose from 15 to 10mg/kg (see Methods). **Protocol amendment was made to substitute temsirolimus for orally-administered everolimus at a dose of 7.5mg once daily (see Methods).
FIGURE 2.
FIGURE 2.. Survival Outcomes in Patients with TNBC Receiving Neoadjuvant DAT/DAE.
(A) Kaplan-Meier plot of event-free survival for all patients. Dashed lines represent the upper and lower bounds of the 95% confidence interval (CI); (B) Kaplan-Meier plot of metastasis-free survival for all patients. Dashed lines represent the upper and lower bounds of the 95% CI; (C) Kaplan-Meier plot of overall survival for all patients. Dashed lines represent the upper and lower bounds of the 95% CI.
See this image and copyright information in PMC

References

    1. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384 (9938):164–172. doi: 10.1016/S0140-6736(13)62422-8 - DOI - PubMed
    1. Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, Smith BL, Alexander B, Moy B, Isakoff SJ, Parmigiani G, Trippa L, Bardia A (2020) Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. Clin Cancer Res 26 (12):2838–2848. doi: 10.1158/1078-0432.CCR-19-3492 - DOI - PMC - PubMed
    1. Huang M, O’Shaughnessy J, Zhao J, Haiderali A, Cortes J, Ramsey SD, Briggs A, Hu P, Karantza V, Aktan G, Qi CZ, Gu C, Xie J, Yuan M, Cook J, Untch M, Schmid P, Fasching PA (2020) Association of Pathologic Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-Analysis. Cancer Res 80 (24):5427–5434. doi: 10.1158/0008-5472.CAN-20-1792 - DOI - PubMed
    1. Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, Walls A, Bousamra A, Ramineni M, Sinn B, Hunt K, Buchholz TA, Valero V, Buzdar AU, Yang W, Brewster AM, Moulder S, Pusztai L, Hatzis C, Hortobagyi GN (2017) Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol 35 (10):1049–1060. doi: 10.1200/JCO.2015.63.1010 - DOI - PMC - PubMed
    1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25 (28):4414–4422. doi: 10.1200/JCO.2007.10.6823 - DOI - PubMed

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