HER2 Mutation Status in Japanese HER2-negative Breast Cancer Patients

Endo, Yumi; Dong, Yanmei; Yoshimoto, Nobuyasu; Asano, Tomoko; Hato, Yukari; Yamashita, Hiroko; Sato, Shinya; Takahashi, Satoru; Fujii, Yoshitaka; Toyama, Tatsuya

doi:10.1093/jjco/hyu053

Cited by 11 publications

(12 citation statements)

References 13 publications

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“…Regarding the other mutations found in our series, the p.I767M mutation was also not functionally characterized as oncogenic, but appeared sensitive to conventional anti-ERBB2 drugs (trastuzumab, lapatinib, neratinib) [14]; the p.S310Y mutation has been functionally characterized as activating mutations that sensitize cancer cells to ERBB2 inhibitors [13]. Interestingly, the mutational spectrum of ERBB2 of ILC reported in this study is distinct from that reported previously by studies carried out on Asian populations, suggesting a possible influence of ethnic factors on the ERBB2 mutation spectrum [24, 27, 28]. Notably, a case-report described the spectacular response to lapatinib for a metastatic ILC patient harboring a rare ERBB2 mutation (p.L869Q) [17].…”

Section: Discussionmentioning

confidence: 70%

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

et al. 2016

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ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.

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Section: Discussionmentioning

confidence: 70%

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

et al. 2016

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“…Patients with HER-2-mutant NSCLC were also reported to have achieved disease control with anti-HER-2 therapy [108,109]. Similar outcome of HER-2-targeted therapy has also been achieved in breast cancer patients with HER-2-mutantions [103,110]. Notably, in Bose's research, all HER-2 mutations including mutation L755S which is resistant to lapatinib, exhibited sensitivity to the irreversible HER-2 inhibitor, neratinib [23].…”

Section: The Therapy Methods To These Her-2 Mutationsmentioning

confidence: 96%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.

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“…Human epidermal growth factor receptor 2 somatic mutations were initially identified in the tyrosine kinase domain of the HER2 gene in breast cancer patients in 2006 . Recently, such mutations have been identified in HER2‐negative breast cancer patients by sequencing assays, including whole‐cancer genome sequencing . Although the mutation rate of this gene is very low (<2%), in vitro and in vivo experiments have shown that some somatic mutations can activate the HER2 signaling pathway in HER2‐negative cells and that these cells are sensitive to some HER2‐targeted drugs .…”

mentioning

confidence: 99%

“…(14) Recently, such mutations have been identified in HER2-negative breast cancer patients by sequencing assays, including whole-cancer genome sequencing. (14)(15)(16)(17)(18)(19)(20)(21) Although the mutation rate of this gene is very low (<2%), in vitro and in vivo experiments have shown that some somatic mutations can activate the HER2 signaling pathway in HER2-negative cells and that these cells are sensitive to some HER2-targeted drugs. (22)(23)(24)(25) These findings suggest that HER2 somatic mutations represent an alternative mechanism for the activation of HER2 in HER2-negative breast cancers, raising an interesting question of whether somatic mutations in HER2-negative breast cancer patients influence the clinical outcome.…”

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confidence: 99%

HER2 somatic mutations are associated with poor survival in HER2‐negative breast cancers

Wang

Sheng

et al. 2017

Cancer Science

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It is well documented that human epidermal growth factor receptor 2 (HER2) overexpression/amplification is associated with poor survival in breast cancer patients. However, it is largely unknown whether HER2 somatic mutations are associated with survival in HER2‐negative breast cancer patients. Here, we identified HER2 somatic mutations in tumors from 1348 unselected breast cancer patients by sequencing the entire HER2 coding region. All of these mutations were tested for in corresponding blood samples to determine whether they were somatic or germline mutations. We further investigated the associations between HER2 somatic mutations and recurrence‐free survival and distant recurrence‐free survival in this cohort of patients. We found that 27 of 1348 (2.0%) of these patients carried a HER2 somatic mutation. In vitro experiments indicated that some of the novel mutations and those with unknown functions increased HER2 activity. HER2 status was available for 1306 patients, and the HER2 somatic mutation rates in HER2‐positive (n = 353) and HER2‐negative breast cancers (n = 953) were 1.4% and 2.3%, respectively. Among the HER2‐negative patients, those with a HER2 somatic mutation had a significantly worse recurrence‐free survival (unadjusted hazard ratio = 2.67; 95% confidence interval, 1.25–5.72, P = 0.002) and distant recurrence‐free survival (unadjusted hazard ratio = 2.50; 95% confidence interval, 1.10–5.68, P = 0.004) than those with wild‐type HER2. Taken together, our findings suggested that HER2 somatic mutations occur at a higher frequency in HER2‐negative breast cancer, and HER2‐negative breast cancer patients with these mutations have poor survival. Therefore, HER2‐negative patients with a HER2 somatic mutation are potentially good candidates for HER2‐targeted therapy.

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HER2 Mutation Status in Japanese HER2-negative Breast Cancer Patients

Cited by 11 publications

References 13 publications

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

HER2 somatic mutations are associated with poor survival in HER2‐negative breast cancers

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