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

被引：92

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

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