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12-04-2023 | Mastectomy | Research

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

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

Published in: Investigational New Drugs | Issue 3/2023

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Abstract. …

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. https://doi.org/10.1016/S0140-6736(13)62422-8CrossRefPubMed

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. https://doi.org/10.1158/1078-0432.CCR-19-3492CrossRefPubMedPubMedCentral

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. https://doi.org/10.1158/0008-5472.CAN-20-1792CrossRefPubMed

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. https://doi.org/10.1200/JCO.2015.63.1010CrossRefPubMedPubMedCentral

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. https://doi.org/10.1200/JCO.2007.10.6823CrossRefPubMed

Yau C, van der Noordaa M, Wei J, Osdoit M, Reyal F, Hamy A-S, Lae M, Martin M, del Monte M, Boughey JC, Gould R, Wesseling J, Steenbruggen T, van Seijen M, Sonke G, Edge S, Sammut S-J, Provenzano E, Abraham J, Hall P, Graham A, Mackintosh L, Cameron D, Wang A, Sharma P, Cole K, Pusztai L, Kim M-O, van ‘t Veer L, Esserman L, Symmans WF (2020) Abstract GS5-01: Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis. Cancer Research 80 (4 Supplement):GS5-01-GS05-01. doi:https://doi.org/10.1158/1538-7445.Sabcs19-gs5-01

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767. https://doi.org/10.1172/JCI45014CrossRefPubMedPubMedCentral

Lehmann BD, Pietenpol JA (2014) Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 232(2):142–150. https://doi.org/10.1002/path.4280CrossRefPubMedPubMedCentral

Yu KD, Zhu R, Zhan M, Rodriguez AA, Yang W, Wong S, Makris A, Lehmann BD, Chen X, Mayer I, Pietenpol JA, Shao ZM, Symmans WF, Chang JC (2013) Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res 19(10):2723–2733. https://doi.org/10.1158/1078-0432.CCR-12-2986CrossRefPubMedPubMedCentral

10.

Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (2016) Refinement of Triple-Negative breast Cancer Molecular Subtypes: implications for Neoadjuvant Chemotherapy Selection. PLoS ONE 11(6):e0157368. https://doi.org/10.1371/journal.pone.0157368CrossRefPubMedPubMedCentral

11.

Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C, He X, Weigman V, Fan C, Palazzo J, Hortobagyi GN, Nolden LK, Wang NJ, Valero V, Gray JW, Perou CM, Mills GB (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69(10):4116–4124. https://doi.org/10.1158/0008-5472.CAN-08-3441CrossRefPubMedPubMedCentral

12.

Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, Hollier BG, Ram PT, Lander ES, Rosen JM, Weinberg RA, Mani SA (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A 107(35):15449–15454. https://doi.org/10.1073/pnas.1004900107CrossRefPubMedPubMedCentral

13.

Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68. https://doi.org/10.1186/bcr2635CrossRefPubMedPubMedCentral

14.

Paplomata E, O’Regan R (2014) The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol 6(4):154–166. https://doi.org/10.1177/1758834014530023CrossRefPubMedPubMedCentral

15.

Coussy F, El Botty R, Lavigne M, Gu C, Fuhrmann L, Briaux A, de Koning L, Dahmani A, Montaudon E, Morisset L, Huguet L, Sourd L, Painsec P, Chateau-Joubert S, Larcher T, Vacher S, Melaabi S, Salomon AV, Marangoni E, Bieche I (2020) Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J Hematol Oncol 13(1):13. https://doi.org/10.1186/s13045-020-0846-yCrossRefPubMedPubMedCentral

16.

Ortega MA, Fraile-Martinez O, Asunsolo A, Bujan J, Garcia-Honduvilla N, Coca S (2020) Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR. J Oncol 2020:9258396. doi:https://doi.org/10.1155/2020/9258396

17.

Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109(8):2784–2789. https://doi.org/10.1073/pnas.1018866109CrossRefPubMedPubMedCentral

18.

Wargotz ES, Norris HJ (1989) Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma. Hum Pathol 20(7):628–635. https://doi.org/10.1016/0046-8177(89)90149-4CrossRefPubMed

19.

Wargotz ES, Deos PH, Norris HJ (1989) Metaplastic carcinomas of the breast. II. Spindle cell carcinoma. Hum Pathol 20(8):732–740. https://doi.org/10.1016/0046-8177(89)90065-8CrossRefPubMed

20.

Wargotz ES, Norris HJ (1989) Metaplastic carcinomas of the breast. III. Carcinosarcoma Cancer 64(7):1490–1499. https://doi.org/10.1002/1097-0142(19891001)64:7<1490::aid-cncr2820640722>3.0.co;2-lCrossRefPubMed

21.

Wargotz ES, Norris HJ (1990) Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin. Cancer 65(2):272–276. https://doi.org/10.1002/1097-0142(19900115)65:2<272::aid-cncr2820650215>3.0.co;2-6CrossRefPubMed

22.

Wargotz ES, Norris HJ (1990) Metaplastic carcinomas of the breast: V. Metaplastic carcinoma with osteoclastic giant cells. Hum Pathol 21(11):1142–1150. https://doi.org/10.1016/0046-8177(90)90151-tCrossRefPubMed

23.

Bellino R, Arisio R, D’Addato F, Attini R, Durando A, Danese S, Bertone E, Grio R, Massobrio M (2003) Metaplastic breast carcinoma: pathology and clinical outcome. Anticancer Res 23(1B):669–673PubMed

24.

Zhang Y, Toy KA, Kleer CG (2012) Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol 25(2):178–184. https://doi.org/10.1038/modpathol.2011.167CrossRefPubMed

25.

Hennessy B, Giordano S, Broglio K, Hortobagyi GN, Valero V (2005) Sarcomatoid (metaplastic) carcinoma of the breast: the U.T. M.D. Anderson Cancer Center (MDACC) and SEER database experience. J Clin Oncol 23(16suppl):614–614. https://doi.org/10.1200/jco.2005.23.16_suppl.614CrossRef

26.

Hennessy BT, Giordano S, Broglio K, Duan Z, Trent J, Buchholz TA, Babiera G, Hortobagyi GN, Valero V (2006) Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol 17(4):605–613. https://doi.org/10.1093/annonc/mdl006CrossRefPubMed

27.

Bae SY, Lee SK, Koo MY, Hur SM, Choi MY, Cho DH, Kim S, Choe JH, Lee JE, Kim JH, Kim JS, Nam SJ, Yang JH (2011) The prognoses of metaplastic breast cancer patients compared to those of triple-negative breast cancer patients. Breast Cancer Res Treat 126(2):471–478. https://doi.org/10.1007/s10549-011-1359-8CrossRefPubMed

28.

Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, Hess KR, Herbrich SM, Valero V, Albarracin C, Litton JK, Chavez-MacGregor M, Ibrahim NK, Murray JL 3rd, Koenig KB, Hong D, Subbiah V, Kurzrock R, Janku F, Moulder SL (2017) Targeting the PI3K/AKT/mTOR pathway for the treatment of Mesenchymal Triple-Negative breast Cancer: evidence from a phase 1 trial of mTOR inhibition in Combination with Liposomal Doxorubicin and Bevacizumab. JAMA Oncol 3(4):509–515. https://doi.org/10.1001/jamaoncol.2016.5281CrossRefPubMed

29.

Basho RK, Yam C, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, Hess KR, Valero V, Albarracin C, Litton JK, Chavez-MacGregor M, Hong D, Kurzrock R, Hortobagyi GN, Janku F, Moulder SL (2018) Comparative effectiveness of an mTOR-Based systemic therapy regimen in Advanced, Metaplastic and Nonmetaplastic Triple-Negative breast Cancer. Oncologist 23(11):1300–1309. https://doi.org/10.1634/theoncologist.2017-0498CrossRefPubMedPubMedCentral

30.

Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2014) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical Oncology/College of american pathologists clinical practice guideline update. Arch Pathol Lab Med 138(2):241–256. https://doi.org/10.5858/arpa.2013-0953-SACrossRefPubMed

31.

Yam C, Yen EY, Chang JT, Bassett RL Jr, Alatrash G, Garber H, Huo L, Yang F, Philips AV, Ding QQ, Lim B, Ueno NT, Kannan K, Sun X, Sun B, Parra Cuentas ER, Symmans WF, White JB, Ravenberg E, Seth S, Guerriero JL, Rauch GM, Damodaran S, Litton JK, Wargo JA, Hortobagyi GN, Futreal A, Wistuba II, Sun R, Moulder SL, Mittendorf EA (2021) Immune phenotype and response to Neoadjuvant Therapy in Triple-Negative breast Cancer. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-21-0144CrossRefPubMedPubMedCentral

32.

Sinn HP, Kreipe H (2013) A Brief Overview of the WHO Classification of Breast Tumors, 4th Edition, Focusing on Issues and Updates from the 3rd Edition. Breast Care (Basel) 8 (2):149–154. doi:https://doi.org/10.1159/000350774

33.

Gan X, Wang J, Wang C, Sommer E, Kozasa T, Srinivasula S, Alessi D, Offermanns S, Simon MI, Wu D (2012) PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and cell migration downstream of Galpha12. Nat Cell Biol 14(7):686–696. https://doi.org/10.1038/ncb2507CrossRefPubMedPubMedCentral

34.

Saxton RA, Sabatini DM (2017) mTOR Signaling in Growth, Metabolism, and Disease. Cell 169(2):361–371. https://doi.org/10.1016/j.cell.2017.03.035CrossRefPubMed

35.

Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399. https://doi.org/10.1038/nature10933CrossRefPubMed

36.

Pascual J, Turner NC (2019) Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann Oncol 30(7):1051–1060. https://doi.org/10.1093/annonc/mdz133CrossRefPubMed

37.

Al-Batran SE, Guntner M, Pauligk C, Scholz M, Chen R, Beiss B, Stopatschinskaja S, Lerbs W, Harbeck N, Jager E (2010) Anthracycline rechallenge using pegylated liposomal doxorubicin in patients with metastatic breast cancer: a pooled analysis using individual data from four prospective trials. Br J Cancer 103(10):1518–1523. https://doi.org/10.1038/sj.bjc.6605961CrossRefPubMedPubMedCentral

38.

Al-Batran SE, Bischoff J, von Minckwitz G, Atmaca A, Kleeberg U, Meuthen I, Morack G, Lerbs W, Hecker D, Sehouli J, Knuth A, Jager E (2006) The clinical benefit of pegylated liposomal doxorubicin in patients with metastatic breast cancer previously treated with conventional anthracyclines: a multicentre phase II trial. Br J Cancer 94(11):1615–1620. https://doi.org/10.1038/sj.bjc.6603158CrossRefPubMedPubMedCentral

Title: Targeting chemotherapy resistance in mesenchymal triple-negative breast cancer: a phase II trial of neoadjuvant angiogenic and mTOR inhibition with chemotherapy
Authors: Nour Abuhadra
Ryan Sun
Roland L. Bassett Jr
Lei Huo
Jeffrey T. Chang
Mediget Teshome
Alyson R. Clayborn
Jason B. White
Elizabeth E. Ravenberg
Beatriz E. Adrada
Rosalind P. Candelaria
Wei Yang
Qingqing Ding
W. Fraser Symmans
Banu Arun
Senthil Damodaran
Kimberly B. Koenig
Rachel M. Layman
Bora Lim
Jennifer K. Litton
Alastair Thompson
Naoto T. Ueno
Helen Piwnica-Worms
Gabriel N. Hortobagyi
Vicente Valero
Debu Tripathy
Gaiane M. Rauch
Stacy Moulder
Clinton Yam
Publication date: 12-04-2023
Publisher: Springer US
Keywords: Mastectomy
Breast Cancer
Breast Cancer
Bevacizumab
Everolimus
Cytostatic Therapy
Published in: Investigational New Drugs / Issue 3/2023
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-023-01357-4

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