Durable Response of Human Epidermal Growth Factor Receptor-2-Positive Gastric Adenosquamous Carcinoma to Trastuzumab-Based Chemotherapy

Here, we report a patient with gastric adenosquamous carcinoma (ASC) with human epidermal growth factor receptor-2 (HER2) overexpression who was successfully treated with trastuzumab-based chemotherapy. The patient was a 66-year-old man preoperatively diagnosed with gastric adenocarcinoma with no evidence of distant metastases. On histopathological examination, the curatively resected tumor was identified as ASC with mixed adenocarcinoma and squamous cell carcinoma components. Multiple liver metastases developed 2.5 months after surgery. Because immunohistochemical staining for HER2 was strong in both components, combination chemotherapy with capecitabine, cisplatin, and trastuzumab was initiated. A partial response was confirmed after 6 treatment cycles and PET and CT scans performed after 13 cycles revealed disease resolution with no uptake in the metastatic lesions. No evidence of disease progression has been observed 16 months after initial chemotherapy. This report suggests the potential utility of trastuzumab-based chemotherapy for HER2-positive gastric ASC.Key Words: Adenosquamous carcinoma, Stomach, Human epidermal growth factor receptor-2, Trastuzumab     

Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis

BackgroundTo determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.Patients and methodsFormalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan–Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive.ResultsSeventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44–1.14; P = 0.194).ConclusionsApproximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.     

A HER2-mutant patient with late-stage duodenal adenocarcinoma benefited from anti-HER2 therapy and PD-1 inhibition: a case report

Duodenal adenocarcinoma (DA) is a subtype of small bowel adenocarcinoma (SBA). Compared with gastrointestinal cancers such as colorectal cancer and gastric cancer, SBA is less common. For patients with advanced and metastatic DA, chemotherapies are usually extrapolated from colorectal cancer and gastric cancer but the therapeutic effects remain undefined. Herein, we reported a 50-year-old female patient whom was diagnosed as stage IV DA with metastasis to both lungs and retroperitoneal lymph nodes. The next generation sequencing (NGS) using a panel consisting of 168 cancer related genes revealed amplification of the HER2/ERBB2 gene which has been a well-recognized therapeutic target among various tumor types. The anti-HER2 targeted therapy trastuzumab was used in combination with XELOX (oxaliplatin and capecitabine) as the first line treatment. The patient achieved partial response (PR) and had progression-free survival (PFS) of six months. After progressive disease (PD), the patient started the second line treatment with trastuzumab and PD1 inhibitors and remained stable disease (SD) with PFS for three months. The use of trastuzumab in neoadjuvant and adjuvant settings have been reported in sporadic cases. To the best of our knowledge, it is the first report to use anti-HER2 therapy and PD-1 inhibition as systemic therapy for advanced DA patients.     

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma

Background:

Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma.

Methods:

The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours.

Results:

Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis.

Conclusion:

The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.     

Targeting HER2 in the treatment of non-small cell lung cancer

Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC.     

抗HER2治疗在转移性结直肠癌中的研究进展

结直肠癌(Colorectal cancer, CRC)是世界第三大常见癌症和第二大癌症相关死亡原因,严重威胁人类生命健康。尽管接受早期诊断和治疗,仍有相当部分结直肠癌患者因发生转移而预后较差。针对结直肠癌分子多样性的研究不但可指导预后,对患者个体化管理亦有重要参考意义。人表皮生长因子受体2(Human epidermal growth factor receptor-2,HER2)在乳腺癌、胃癌等多种恶性肿瘤中表达,抗HER2治疗能有效改善HER2阳性晚期乳腺癌、胃癌患者的预后。HER2作为转移性结直肠癌(metastatic colorectal cancer, mCRC)新兴的生物标志物近年来也备受关注。本文就目前HER2阳性mCRC的诊疗现状研究进展做一综述,以期为临床诊断、药物选择等提供参考。     

Optimal management of gastroesophageal junction cancer

Although recent decades have witnessed incremental improvements in the treatment of gastroesophageal junction (GEJ) carcinoma, outcomes remain modest. For locally advanced esophageal cancer, the addition of chemotherapy and/or radiation to surgery is considered the standard of care. Chemotherapy remains the primary treatment for metastatic disease and improves survival over best supportive care. However, the prognosis for patients with GEJ cancers, which are treated along the same paradigms as esophageal and gastric carcinomas, remain poor because of the emergence of chemoresistance and limited targeted therapeutic approaches, which include agents that target the HER2 and vascular endothelial growth factor pathways. Evaluation of immune checkpoint inhibitors in the chemorefractory setting have confirmed the activity of immunotherapy in esophagogastric cancer. Ongoing immunotherapeutic strategies are being evaluated in both the locally advanced and metastatic settings. This review focuses on the treatment of locally advanced and metastatic GEJ carcinomas, which encompass all tumors that have an epicenter within 5 cm proximal or distal to the anatomical Z-line (Siewert classification). Because the vast majority of GEJ tumors are adenocarcinoma, the management of adenocarcinoma is the focus of this review. Evolving approaches and areas of clinical equipoise are discussed.     

HER2在胃癌中的研究进展

胃癌病理发展过程复杂,预后较差,化疗效果欠佳。人类表皮生长因子受体2（HER2）与胃癌的相关性、分子靶向治疗是近年来研究的热点,可为探索胃癌的发病机制、临床治疗及预防提供依据。本文就HER2家族的结构、功能、信号转导、针对HER2的靶向药物在胃癌治疗中的研究进展做一综述。     

HER2 Status in Gastric Cancer: Comparison between Primary and Distant Metastatic Disease

HER2 (human epidermal growth factor receptor-2) assessment in histological samples of gastric cancer is essential to determine which patients might benefit from trastuzumab therapy. HER2 is often evaluated in primary tumor even if trastuzumab therapy is used to treat metastatic disease. However, the exact relationship in terms of HER2 status between primary and metastatic tumors has not been fully clarified. We aimed to evaluate the HER2 status concordance between primary gastric cancer and corresponding distant metastasis. HER2 status was evaluated by IHC (immunohistochemistry) and/or FISH ( fluorescence in situ hybridization) in 41 patients in primary gastric cancer and in paired metastasis. HER2 was assessed according scoring criteria applied in clinical approach. HER2 positivity was found in 14,6 % primary tumors and in 24,4%corresponding metastasis. HER2 concordance rate between primary and metastasis was 80,5 % (K-value = 0,388). Eight/41 (19,5 %)cases resulted discordant: 6 patients with metastatic HER2 positive lesions were found HER2 negative in primary cancers while 2 patient HER2 positive in primary lesion showed a negative conversion in metastasis. Our results showed a good concordance in terms of HER2 status between primary and metastatic lesions, as well as in biopsy and surgical removed specimens. However, the higher rate of HER2 positive status found in metastatic lesions underlined the importance of HER2 assessment in all samples obtained from different sites of gastric cancer disease.     

Antitumor activity of pan‐HER inhibitors in HER2‐positive gastric cancer

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti‐human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti‐HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2‐positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan‐HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2‐amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin‐like growth factor‐1 receptor (IGF‐1R), were less sensitive to pan‐HER inhibitors. A combination therapy consisting of pan‐HER inhibitors and an IGF‐1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2‐amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF‐1R‐targeting therapy can overcome drug insensitiveness in HER2‐amplified gastric cancer.     

Combination of novel HER2‐targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2‐positive gastric cancer

The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti‐cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–25% of breast and gastric cancer patients, and HER2‐targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2‐positive gastric cancer. Here, we describe the development of 1E11, a HER2‐targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2‐overexpressing gastric cancer cell lines NCI‐N87 and OE‐19. The two antibodies bind to sub‐domain IV of the receptor, but have non‐overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2‐positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2‐overexpressing gastric cancers.     

HER2 Activating Mutations in Estrogen Receptor Positive Breast Cancer

Purpose of Review

HER2 activating mutations are a new, druggable mutation identified by next-generation DNA sequencing (NGS) of breast cancer. Here, we review the recent data on the diagnosis and treatment of HER2 mutated, metastatic breast cancer.

Recent Findings

Pre-clinical studies have shown that HER2 activating mutations accelerate tumor growth and can be inhibited by HER2 targeted drugs, including trastuzumab and the second-generation, pan-HER tyrosine kinase inhibitor, neratinib. HER2 mutations can be diagnosed by NGS testing on either a tumor biopsy or circulating tumor DNA obtained from peripheral blood. Case reports provided initial evidence that HER2 targeted therapies can effectively treat patients with HER2 mutated, metastatic breast cancer. Two phase II clinical trials, MutHER and SUMMIT, both demonstrate that neratinib monotherapy has clinical efficacy for these patients, with clinical benefit rate of 31–40%.

Summary

HER2 targeted therapies are effective for HER2 mutated breast cancer but emergence of drug resistance remains a problem. Clinical trials are now testing neratinib-containing drug combination regimens for HER2 mutated, metastatic breast cancer patients.

     

ErbB2／Grb2／mTOR通路在胃癌发生发展中的作用

目的：检测ErbB2／neu、Grb2和mTOR胃癌中的表达并探讨ErbB2／Grb2／mTOR通路在胃癌发生发展中的作用。方法：构建含有1072例胃癌的组织芯片，利用免疫组化检测ErbB2／neu、Grb2和mTOR在胃癌中的表达。结果：ErbB2／neu、Grb2和mTOR在胃癌中的表达率分别为30．2％、47．5％和50．8％。ErbB2／neu和Grb2的过度表达与年龄（〉60岁）、肿瘤部位、肿瘤类型和高分化相关（P〈0．01）；mTOR的过度表达与肿瘤部位、肿瘤类型、高分化、T分期和TNM分期相关（P〈0．05）。Spearman相关性检验显示，3个蛋白两两之间存在显著相关（P〈0．001）。单因素生存分析表明，Grb2和mTOR与预后有关（P=0．0067，P=0．0001）；而在Cox回归多因素分析中，roTOR与预后有关（P=0．046）。结论：ErbB2／Grb2／mTOR通路在胃癌的发生发展中起到极其重要的作用，mTOR还可能作为胃癌患者预后的独立指标。3个蛋白可以作为胃癌治疗的靶点，继而为胃癌的治疗开拓新的思路。     

HER2 and gastric cancer: a novel therapeutic target for trastuzumab

HER2 protein overexpression by immunohistochemistry (IHC) and/or erB2 gene amplification by in situ hybridization (ISH) was detected in 4-28% of gastric or gastro-oesophageal junction (GOJ) cancers. Most studies have shown that HER2-overexpressing gastric cancers were worse prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2 with known efficacy in patients with HER2+ early or metastatic breast cancer. The international randomized trial ToGA study showed the superiority of the combination of trastuzumab with chemotherapy doublet fluoropyrimidine (5-FU or capecitabine) plus cisplatin (FP) every three weeks compared with chemotherapy alone in terms of overall survival : 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. Trastuzumab plus FP chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or GOJ cancer. All these cancers should be tested for HER2 on paraffin block resection or biopsy specimens of the primary tumour or metastases. Endoscopic gastric biopsies should be multiple. The IHC should be the initial test. The standardized immunohistochemical scoring system differs from that recommended for breast cancer given the heterogeneity of HER2 expression and the frequency of incomplete membranous staining in gastric cancers. Equivocal IHC2+ tumours should be tested by ISH with two tools: fluorescence in situ hybridization (FISH) or bright field in situ hybridization (SISH). The perspectives are the assessment of trastuzumab in the perioperative and adjuvant setting, the development of novel anti-HER2 drugs and research into mechanisms of resistance and predictive molecular markers.     

New therapies in HER2-positive breast cancer: A major step towards a cure of the disease?

Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches.     

胃癌高通量测序临床应用中国专家共识

胃癌是消化系统最常见的恶性肿瘤之一，异质性较强，具有复杂的分子特征。HER2、MSI、TMB和NTRK融合等肿瘤相关标志物及分子病理学检测革新了胃癌诊疗模式。根据患者的病理特征和基因检测结果进一步筛选靶向和免疫药物的潜在获益人群，是胃癌精准治疗的未来发展方向。高通量测序（next-generation sequencing,NGS）在胃癌诊断、治疗方案选择、预后监测中发挥着日益重要的作用。然而，国内目前对胃癌NGS的理解与应用尚有不足。中国抗癌协会胃癌专业委员会专家组基于循证医学证据制定《胃癌高通量测序临床应用中国专家共识》，旨在提高中国临床医生与患者对于胃癌NGS的认识，以指导与规范其在国内的临床应用。     

Human Epidermal Growth Factor Receptor 2-Positive Duodenal Adenocarcinoma: A Case Report and Review of the Literature

Duodenal adenocarcinoma is a rare malignancy and carries a poor prognosis. The role of adjuvant therapy and the optimal chemotherapy regimen remain largely unclear. Treatment with trastuzumab results in prolonged survival in gastroesophageal cancer if human epidermal growth factor receptor 2 (HER2) is overexpressed or amplified in tumor cells. However, unlike gastric adenocarcinomas, duodenal cancers seem to rarely harbor HER2 amplification or overexpression. We report the case of a patient with HER2-positive stage III duodenal adenocarcinoma who has received adjuvant chemotherapy including trastuzumab.Key Words: Duodenal adenocarcinoma, Trastuzumab, Human epidermal growth factor receptor 2 amplification     

胃癌原发灶和淋巴结转移灶HER2表达的临床意义

目的 观察HER2在胃癌原发灶和淋巴结转移灶中的表达及其临床意义.方法 选取胃癌患者140例,其中淋巴结转移94例.采集胃癌患者的原发灶、淋巴结转移灶及癌旁组织,采用免疫组织化学法(Elivision)方法检测3种组织中HER2蛋白表达情况.结果 140例胃癌原发灶组织中HER2蛋白阳性表达与胃癌TNM分期、浸润深度及淋巴结转移有关(P<0.05),而与患者性别、年龄和分化程度无关(P>0.05),癌旁组织中HER2表达与性别、年龄、分化程度、TNM分期、浸润深度及淋巴结转移均无关(P>0.05);HER2蛋白在胃癌原发灶、淋巴结转移灶中表达水平均高于癌旁组织,差异有统计学意义,而94例淋巴结转移灶和对应的胃癌原发灶中HER2表达的差异无统计学意义;94例有淋巴结转移的患者淋巴结转移灶与原发灶HER2表达一致率为89.4%,两类标本HER2表达状态具有一致性(Z=6.386,P<0.001).结论 胃癌HER2蛋白的阳性表达与胃癌TNM分期、浸润深度及淋巴结转移有关,提示HER2的表达与胃癌的浸润转移有关;胃癌原发灶和淋巴结转移灶HER2的表达具有较好的一致性,患者在不能获取原发病灶的情况下,检测转移灶中HER-2可能为靶向治疗的选择提供依据,为晚期胃癌患者带来希望.     

Relation of HER2 status and prognosis in gastric cancer patients

Human epidermal growth factor receptor-2 (HER2) became one of the most important biomarkers for gastric cancer patients with the results of ToGA trial which proved the benefits of trastuzumab treatment in HER2-positive advanced or recurrent gastric cancer patients. Many investigations have been conducted on HER2 as a prognostic factor. Although there have been no universal conclusions, the positive result of HER2 status appears to be poor prognostic factor according to current evidences. All the studies have encountered problems such as small sample size, diversity of patient characteristics,methods of HER2 tests and diagnosis of HER2 status. Furthermore, few studies were conducted in advanced or recurrent gastric cancer patients. Biomarker analysis including HER2 status on the patients enrolled in ACTS-GC trial which evaluated S-1 in resectable gastric cancer patients is underway, and we are planning biomarker analysis of HER2 status as a prognostic factor on advanced or recurrent gastric cancer patients. These results would clarify the role of HER2 as a prognostic factor.     

HER2 Positive and HER2 Negative Classical Type Invasive Lobular Carcinomas: Comparison of Clinicopathologic Features

Human epidermal growth factor receptor 2 (HER2) positive (+) classical type invasive lobular carcinoma (cILC) of the breast is extremely rare and its clinicopathologic features have not been well characterized. We compared features of HER2(+) and HER2 negative (−) cILCs. A total of 29 cases were identified from the clinical database at our institution from 2011-2019; 9 were HER2(+) cILC tumors and 20 were HER2(−) cILC tumors. The results reveal that HER2(+) cILC group had significantly increased Ki-67 expression and reduced estrogen receptor (ER) expression compared to HER2(−) cILC group (both p < 0.05). In addition, HER2(+) cILCs tended to be diagnosed at a younger age and more common in the left breast, and appeared to have a higher frequency of nodal or distant metastases. These clinicopathologic features suggest HER2(+) cILC tumors may have more aggressive behavior than their HER2(−) counterpart although both groups of tumors showed similar morphologic features. Future directions of the study: (1) To conduct a multi-institutional study with a larger case series of HER2(+) cILC to further characterize its clinicopathologic features; (2) to compare molecular profiles by next generation sequencing (NGS) assay between HER2(+) cILC and HER2(−) cILC cases to better understand tumor biology of this rare subset of HER2(+) breast cancer; and (3) to compare molecular characteristics of HER2(+) cILC and HER2(+) high grade breast cancer in conjunction with status of tumor response to anti-HER2 therapy to provide insight to management of this special type of low grade breast cancer to avoid unnecessary treatment and related toxicity