HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Prat, Aleix; Pascual, Tomás; Angelis, Carmine De; Gutiérrez, Carolina; Llombart-Cussac, Antonio; Wang, Tao; Cortés, Javier; Rexer, Brent N.; Paré, Laia; Forero, Andres; Wolff, Antonio C.; Morales, Serafín; Adamo, Bárbara; Brasó-Maristany, Fara; Vidal, María; Veeraraghavan, Jamunarani; Krop, Ian E.; Galván, Patricia; Pavlick, Anne C.; Bermejo, Begoña; Izquierdo, Miguel; Rodrik-Outmezguine, Vanessa; Reis‐Filho, Jorge S.; Hilsenbeck, Susan G.; Oliveira, Mafalda; Dieci, Maria Vittoria; Griguolo, Gaia; Fasani, Roberta; Nuciforo, Paolo; Parker, Joel S.; Conte, Pierfranco; Schiff, Rachel; Guarneri, Valentina; Osborne, C. Kent; Rimawi, Mothaffar F.

doi:10.1093/jnci/djz042

Cited by 109 publications

(118 citation statements)

References 23 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…2). An analysis of baseline tumor samples from two clinical trials found that combined analysis of HER2E subtype and ERBB2 mRNA into a single assay identified tumors with high responsiveness to HER2-targeted therapy (7).…”

Section: Introductionmentioning

confidence: 99%

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response

Swain

Tang

Brauer

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41. Patients and Methods: Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization. Results: Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial-mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73. Conclusions: The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.

show abstract

Section: Introductionmentioning

confidence: 99%

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response

Swain

Tang

Brauer

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The clinical value of the HER2-E subtype in HER2+ breast cancer is starting to be elucidated. From a therapeutic perspective, the HER2-E subtype has shown, across 14 clinical trials and ∼2,000 patients, higher sensitivity to anti-HER2-based therapies than the non-HER2-E subtypes [7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, not all HER2-E tumors achieve a complete response following anti-HER2-based therapies.…”

mentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼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.

show abstract

“…"Oncogene addiction" is used to describe tumors fully dependent on HER2 for proliferation and survival. These cancers are often exquisitely sensitive to HER2-directed therapy [16,17], even in the absence of Receptor pathways involved in the progression of breast cancer and mechanism of action of endocrine and targeted therapies. AI = aromatase inhibitor; AKT = protein kinase B; CDK = cyclin-dependent kinase; CoA = coactivator complex; CoR = corepressor complex; E2 = estradiol; EGFR = epidermal growth factor receptor; ER = estrogen receptor; EREs = estrogen receptor elements; ERK = extracellular signal-regulated kinase; HER2 = human epidermal growth factor receptor 2; IGF-1 = insulin-like growth factor 1 receptor; P = phosphorylation; PI3K = phosphatidylinositol 3-kinase; mTOR = mammalian target of rapamycin; Rb = Retinoblastoma protein (tumor suppressor protein); RE = response elements; RTKs = receptor tyrosine kinases; SERD = selective estrogen receptor degrader; SERM = selective estrogen receptor modulator; and TFs = transcription factors (e.g., activator protein 1 (AP-1), specificity protein 1 (SP-1), and E2 factor (E2F).…”

Section: Her2 Itselfmentioning

confidence: 99%

Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature

Thanopoulou

Khader

Caira

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.

show abstract

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Cited by 109 publications

References 23 publications

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response

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

Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature

Contact Info

Product

Resources

About