Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

被引：91

作者：

Braso-Maristany, Fara ^{[1
,2
]}

Griguolo, Gaia ^{[1
,2
,3
,4
]}

Pascual, Tomas ^{[1
,2
,5
]}

Pare, Laia ^{[5
]}

Nuciforo, Paolo ^{[6
,7
]}

Llombart-Cussac, Antonio ^{[8
]}

Bermejo, Begona ^{[9
]}

Oliveira, Mafalda ^{[6
,7
]}

Morales, Serafin ^{[10
]}

Martinez, Noelia ^{[11
]}

Vidal, Maria ^{[1
,2
,5
]}

Adamo, Barbara ^{[1
,2
]}

Martinez, Olga ^{[1
,2
]}

Pernas, Sonia ^{[5
,12
]}

Lopez, Rafael ^{[13
]}

Munoz, Montserrat ^{[1
,2
]}

Chic, Nuria ^{[1
,2
]}

Galvan, Patricia ^{[1
,2
]}

Garau, Isabel ^{[14
]}

Manso, Luis ^{[15
]}

Alarcon, Jesus ^{[16
]}

Martinez, Eduardo ^{[17
]}

Gregorio, Sara ^{[18
]}

Gomis, Roger R. ^{[18
]}

Villagrasa, Patricia ^{[5
]}

Cortes, Javier ^{[7
,19
]}

Ciruelos, Eva ^{[5
,15
]}

Prat, Aleix ^{[1
,2
,5
]}

机构：

[1] Hosp Clin Barcelona, Dept Med Oncol, E-08036 Barcelona, Spain

[2] August Pi & Sunyer Biomed Res Inst IDIBAPS, Translat Genom & Targeted Therapeut Solid Tumors, Carrer Rossello 149-153, Barcelona 08036, Spain

[3] Univ Padua, Dept Surg Oncol & Gastroenterol, Via Giustiniani 2, I-35124 Padua, Italy

[4] IRCCS, Ist Oncol Veneto, Med Oncol 2, Via Gattamelata 64, I-35128 Padua, Italy

[5] SOLTI Breast Canc Res Grp, Carrer Balmes 115, Barcelona 08008, Spain

[6] Vall dHebron Univ Hosp, Passeig Vall dHebron 119-129, Barcelona 08035, Spain

[7] VHIO, Passeig Vall dHebron 119-129, Barcelona 08035, Spain

[8] Hosp Arnau Vilanova, Carrer St Clement 12, Valencia 46015, Spain

[9] Hosp Clin Univ Valencia, Av Blasco Ibanez 17, Valencia 46010, Spain

[10] Hosp Arnau Vilanova, Av Alcalde Rovira Roure 80, Lleida 25198, Spain

[11] Hosp Univ Ramon & Cajal, M-607,Km 9, Madrid 28034, Spain

[12] Inst Catala Oncol, Avinguda Gran Via Hospitalet 199-203, Lhospitalet De Llobregat 08908, Spain

[13] Hosp Clin Univ Santiago, Rua Choupana S-N, Santiago De Compostela 15706, Spain

[14] Hosp Son Llatzer, Ctra Manacor, Palma De Mallorca 07198, Spain

[15] Hosp Univ 12 Octubre, Av Cordoba S-N, Madrid 28041, Spain

[16] Hosp Univ Son Espases, Carretera Valldemossa 79, Palma De Mallorca 07120, Spain

[17] Consorcio Hosp Prov Castellon, Av Dr Clara 19, Castellon De La Plana 12002, Spain

[18] Inst Res Biomed, Carrer Baldiri Reixac 10, Barcelona 08028, Spain

[19] IOB Inst Oncol, Quiron Grp, Placa Alfonso Comin 5, Barcelona 08023, Spain

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

MOLECULAR PORTRAITS; PLUS TRASTUZUMAB; OPEN-LABEL; CHEMOTHERAPY; PREDICTOR; SUBTYPES; MULTICENTER; RISK;

D O I：

10.1038/s41467-019-14111-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, similar to 20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.

引用

页数：11

共 38 条

[1] [Anonymous], CLIN ONCOLOGY
[2] Bianchini G, 2018, ANN ONCOL, V29, P61
[3] Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib
Carey, Lisa A.
Berry, Donald A.
Cirrincione, Constance T.
Barry, William T.
Pitcher, Brandelyn N.
Harris, Lyndsay N.
Ollila, David W.
Krop, Ian E.
Henry, Norah Lynn
Weckstein, Douglas J.
Anders, Carey K.
Singh, Baljit
Hoadley, Katherine A.
Iglesia, Michael
Cheang, Maggie Chon U.
Perou, Charles M.
Winer, Eric P.
Hudis, Clifford A.
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (06) : 542 - +
[4] Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors
Chakrabarty, Anindita
Bhola, Neil E.
Sutton, Cammie
Ghosh, Ritwik
Kuba, Maria Gabriela
Dave, Bhuvanesh
Chang, Jenny C.
Arteaga, Carlos L.
[J]. CANCER RESEARCH, 2013, 73 (03) : 1190 - 1200
[5] Ciruelos E, 2019, CANCER RES, V79, pPD3, DOI [10.1158/0008-5472.CAN-18-3552, DOI 10.1158/0008-5472.CAN-18-3552]
[6] Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study
Conte, P.
Frassoldati, A.
Bisagni, G.
Brandes, A. A.
Donadio, M.
Garrone, O.
Piacentini, F.
Cavanna, L.
Giotta, F.
Aieta, M.
Gebbia, V.
Molino, A.
Musolino, A.
Ferro, A.
Maltoni, R.
Danese, S.
Zamagni, C.
Rimanti, A.
Cagossi, K.
Russo, A.
Pronzato, P.
Giovanardi, F.
Moretti, G.
Lombardo, L.
Schirone, A.
Beano, A.
Amaducci, L.
Bajardi, E. A.
Vicini, R.
Balduzzi, S.
D'Amico, R.
Guarneri, V.
Giarratano, Tommaso
McMahon, Laura
De Salvo, Gian Luca
Dieci, Maria Vittoria
Maiorana, Antonio
Ficarra, Guido
Caggia, Federica
Grisolia, Deborah
Bartolini, Stefania
Lorusso, Vito
Ardito, Raffaele
Tartarone, Alfredo
Vanella, Paola
Taverniti, Cristiana
Porpiglia, Mauro
Spanu, Pier Giorgio
Biglia, Nicoletta
Andreis, Daniele
[J]. ANNALS OF ONCOLOGY, 2018, 29 (12) : 2328 - 2333
[7] Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis
Cortazar, Patricia
Zhang, Lijun
Untch, Michael
Mehta, Keyur
Costantino, Joseph P.
Wolmark, Norman
Bonnefoi, Herve
Cameron, David
Gianni, Luca
Valagussa, Pinuccia
Swain, Sandra M.
Prowell, Tatiana
Loibl, Sibylle
Wickerham, D. Lawrence
Bogaerts, Jan
Baselga, Jose
Perou, Charles
Blumenthal, Gideon
Blohmer, Jens
Mamounas, Eleftherios P.
Bergh, Jonas
Semiglazov, Vladimir
Justice, Robert
Eidtmann, Holger
Paik, Soonmyung
Piccart, Martine
Sridhara, Rajeshwari
Fasching, Peter A.
Slaets, Leen
Tang, Shenghui
Gerber, Bernd
Geyer, Charles E., Jr.
Pazdur, Richard
Ditsch, Nina
Rastogi, Priya
Eiermann, Wolfgang
von Minckwitz, Gunter
[J]. LANCET, 2014, 384 (9938) : 164 - 172
[8] Day C, 2018, ANN ONCOL, V29
[9] Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial
Dieci, M. V.
Prat, A.
Tagliafico, E.
Pare, L.
Ficarra, G.
Bisagni, G.
Piacentini, F.
Generali, D. G.
Conte, P.
Guarneri, V.
[J]. ANNALS OF ONCOLOGY, 2016, 27 (10) : 1867 - 1873
[10] Finn R, 2018, CANCER RES, V78, P2

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