Change in HER2 status after neoadjuvant chemotherapy and the prognostic impact in patients with primary breast cancer

Yoshida, Atsushi; Hayashi, Naoki; Suzuki, Koyu; Takimoto, Masafumi; Nakamura, Seigo; Yamauchi, Hideko

doi:10.1002/jso.24762

Cited by 44 publications

(45 citation statements)

References 28 publications

(59 reference statements)

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“…Similarly, it has been shown that the co‐operation between HER2 and NF‐κB enhanced tumour resistance to radiotherapy (Ahmed, Cao, & Li, ). Therefore, we postulate that the overexpression of HER2 in MCF7 cells confers resistance to NAC, supporting the current regulations in re‐checking HER2 status after NAC (Yoshida et al, ).…”

Section: Discussionsupporting

confidence: 85%

“…MCF7 cells do not express HER2 (Lee, Oesterreich, & Davidson, ) but the recombinant overexpression of HER2 in MCF7 cells leads to intracellular signalling through activation of PI3K‐p110α and thus promoting the phosphorylation of Akt, which consequently induced resistance to several chemotherapy drugs (Knuefermann et al, ). Several reports have shown that HER2 status in breast tumours can be reversed through the course of NAC treatment (Dieci et al, ; Niikura et al, ; Yoshida et al, ). Change of HER2 status from positive to negative in patients with recurring breast cancer was shown to have a poor outcome and low overall survival (Dieci et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Change of HER2 status from positive to negative in patients with recurring breast cancer was shown to have a poor outcome and low overall survival (Dieci et al, ). However, gaining HER2 did not show correlation with disease‐free survival, probably due to the introduction of trastuzumab (Herceptin) in the treatment modalities that improves the treatment strategy (Yoshida et al, ). Therefore, it is crucial to study the molecular changes taking place during NAC, which leads to tumour subtype conversion in order to, eventually, find more precise targets for each subtype.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Al-Zeheimi

Adham

2020

British J Pharmacology

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Background and Purpose: Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes. Experimental Approach: We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC). Key Results: Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κB p65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up-regulated neuropilin-1, oestrogen receptor-α, and EGFR, and activated PI3K/Akt/NF-κB p65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down-regulation of the survival axis and up-regulated BCRP/ABCG2. Co-immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin-1 driving the resistance features.Conclusions and Implications: The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Al-Zeheimi

Adham

2020

British J Pharmacology

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“…It has been postulated that prior exposure to chemotherapy can cause alterations in the EGFR or HER2 pathway [11][12][13]. Molecular alterations have been previously reported in patients with LFS [14], including rare HER2 mutations.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management

et al. 2020

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Germline mutations in TP53, a tumor suppressor gene, are involved in the development of Li-Fraumeni syndrome, a rare disorder that predisposes carriers to multiple tumors. TP53 mutations have been associated with resistance to treatment and poor prognosis. A young female with the pathogenic germline TP53 mutation c.844C > T (p.R282W) was diagnosed with two metachronous breast tumors, one HER2-negative and the other HER2-positive. She was later diagnosed with synchronous glioblastoma, epidermal growth factor receptor-mutated lung adenocarcinoma, and HER2-negative breast cancer metastases. The patient was treated with local therapies, including brain surgery and radiotherapy, lung surgery, and a bilateral mastectomy, as well as with targeted systemic treatment. She proved to be highly sensitive to systemic therapy, and 13 years after the initial diagnosis of breast cancer and 6 years after the diagnosis of the two new primary tumors and recurrence of a prior cancer, she is alive with an excellent performance status. This surprising positive evolution may well be partly due to the pronged multidisciplinary approach to managing her disease and her extraordinary response to treatment: the lung adenocarcinoma showed excellent response to erlotinib; the breast cancer responded extremely well to eribulin and pegylated liposomal doxorubicin; and the glioblastoma has remained in response to surgery and radiotherapy. Despite harboring a TP53 mutation and having multiple tumors, this patient has shown an unexpectedly favorable evolution. The coordinated participation of a multidisciplinary team and the patient's own extraordinarily high sensitivity to systemic treatment played a major role in this evolution.

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“…The mechanisms leading to differential expression of these receptors have not been elucidated. Intra-tumor heterogeneity, molecular changes during the biological evolution of the tumor, the microenvironment or the selection pressure induced by therapies are probably involved as described for HER2 and hormone-receptor positive tumors following chemotherapy [45][46][47][48][49][50][51].…”

Section: Heterogeneity Of Breast Cancer Metastasesmentioning

confidence: 99%

Metastatic Heterogeneity of Breast Cancer: Companion and Theranostic Approach in Nuclear Medicine

Montemagno

Pagès

2020

Cancers

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Breast cancer is the most common malignancy in women throughout the world. Metastatic dissemination to vital organs is the leading cause of breast cancer-related deaths. The treatment of metastases is mainly based on the primary tumor characteristics. However, breast cancer metastases exhibit high heterogeneity leading to different prognosis and therapeutic responses. Getting access to phenotype of metastases would allow better management of patients. The advent of theranostics in nuclear medicine has opened new opportunities for the diagnosis and treatment of cancer patients. The aim of this review is to provide an overview of current knowledge and future directions in nuclear medicine for therapeutic management of metastatic breast cancer patients.

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Change in HER2 status after neoadjuvant chemotherapy and the prognostic impact in patients with primary breast cancer

Abstract: Our results showed that changes in HER2 status did not affect patients' prognosis. Further studies are needed to determine whether HER2-targeting agents can be omitted when loss of HER2-positivity is confirmed after NAC.

Cited by 44 publications

References 28 publications

Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management

Metastatic Heterogeneity of Breast Cancer: Companion and Theranostic Approach in Nuclear Medicine

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