The TRAR gene classifier to predict response to neoadjuvant therapy in HER2‐positive and ER‐positive breast cancer patients: an explorative analysis from the NeoSphere trial

Triulzi, Tiziana; Cosimo, Serena Di; Pieńkowski, Tadeusz; Im, Young‐Hyuck; Bianchi, Giulia; Galbardi, Barbara; Dugo, Matteo; Cecco, Loris De; Tseng, Ling‐Ming; Liu, Mei-Ching; Bermejo, Begoña; Семиглазов, Владимир; Viale, Giulia; Haba-Rodríguez, Juan de la; Oh, Do‐Youn; Poirier, Brigitte; Valagussa, Pinuccia; Gianni, Luca; Tagliabue, Elda

doi:10.1002/1878-0261.13141

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…Even if based on a small sample cohort, our data provided evidence of the predictive value of HER2 mRNA in both ER-positive and ER-negative subgroups of adjuvant trastuzumab-treated patients, supporting the possibility that HER2 predictive value could be relevant mainly in patients with expression of both ER and HER2, especially in an adjuvant treatment setting. This hypothesis is supported by our data on the predictive value of TRAR, in which HER2 and ESR1 are core genes only in ER-positive tumors of the NeoSphere trial [ 33 ], and the data of the Gepar IV trial, which showed that pCR rate continuously rose with increases in HER2 mRNA levels only in ER-positive tumors [ 12 ].…”

Section: Discussionsupporting

confidence: 54%

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

Triulzi

Regondi

Venturelli

et al. 2022

Cancers

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While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors.

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Section: Discussionsupporting

confidence: 54%

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

Triulzi

Regondi

Venturelli

et al. 2022

Cancers

Self Cite

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“…[270][271][272][273] ). Furthermore, gene expressionbased tools for prognostic and predictive purposes are also under evaluation in HER2 + breast cancer, although none of these has yet reached mainstream use 274,275 .…”

Section: Her2 Diagnosticsmentioning

confidence: 99%

Targeting HER2-positive breast cancer: advances and future directions

Swain

Shastry

Hamilton

2022

Nat Rev Drug Discov

398

150

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The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug -the monoclonal antibody trastuzumab -almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2targeted therapy and new therapeutic approaches and agents, including Nature Reviews Drug Discovery Review articlethan half of patients with metastatic HER2 + disease are diagnosed de novo, further demonstrating that most patients presenting with early disease are cured 6 .However, despite this success, metastatic HER2 + tumours inevitably develop resistance, leading to disease progression. As such, the goal of therapy in HER2 + BC is to expand the number of patients cured in the early setting and prevent recurrence. In those HER2 + cancers that do present with de novo stage IV disease or ultimately recur, development of novel therapies is needed as these tumours continue to be dependent on HER2 signalling. Therefore, extensive research is ongoing in the preclinical, translational and clinical arenas to develop original and more potent therapies for this exceptionally sensitive target, HER2.Advances in targeting HER2 include further exploitation of antibody-drug conjugates (ADCs), altering the linkers, payload or antibody scaffold to optimize efficacy 7,8 . Another approach is the development of bispecific antibodies, which use binding of two different HER2 epitopes to maximize efficacy 9 . As immunotherapy has shown benefit in triple-negative breast cancer (TNBC), attempts to mobilize the immune system in HER2 + disease are also ongoing. Immunotherapy is being approached from various angles including administering

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Dual neoadjuvant blockade plus chemotherapy versus monotherapy for the treatment of women with non-metastatic HER2-positive breast cancer: a systematic review and meta-analysis

et al. 2022

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The TRAR gene classifier to predict response to neoadjuvant therapy in HER2‐positive and ER‐positive breast cancer patients: an explorative analysis from the NeoSphere trial

Cited by 4 publications

References 32 publications

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

Targeting HER2-positive breast cancer: advances and future directions

Dual neoadjuvant blockade plus chemotherapy versus monotherapy for the treatment of women with non-metastatic HER2-positive breast cancer: a systematic review and meta-analysis

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