Novel Therapies for the Treatment of HER2-Positive Advanced Breast Cancer: A Canadian Perspective

The advent of anti-HER2 targeted therapies has dramatically improved the outcome of HER2-positive breast cancer; however, resistance to treatment in the metastatic setting remains a challenge, highlighting the need for novel therapies. The arrival of new treatment options and clinical trials examining the efficacy of novel agents may improve outcomes in the metastatic setting, including in patients with brain metastases. In the first-line setting, we can potentially cure a selected number of patients treated with pertuzumab + trastuzumab + taxane. In the second-line setting, clinical trials show that trastuzumab deruxtecan (T-DXd) is a highly effective option, resulting in a shift from trastuzumab emtansine (T-DM1) as the previous standard of care. Moreover, we now have data for patients with brain metastases to show that tucatinib + trastuzumab + capecitabine can improve survival in this higher-risk group and be an effective regimen for all patients in the third-line setting. Finally, we have a number of effective anti-HER2 therapies that can be used in subsequent lines of therapy to improve patient outcomes. This review paper discusses the current treatment options and presents a practical treatment sequencing algorithm in the context of the Canadian landscape.     

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.     

HER2 discordance between paired primary gastric cancer and metastasis:a meta-analysis

Background:A number of stuthes have examined human epidermal growth factor receptor 2(HER2)status in primary gastric cancer(GC) and associated metastasis,some showed their great concordance in HER2 expression,but others demonstrated notable discordance.There is still little consensus on HER2 discordance,therefore,a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis.Methods:PubMed,EMBASE,ASCO and The Cochrane Library were searched for stuthes that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March,2014.Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions.Results:Eighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria.Pooled discordance proportions were 7%[95%confidence interval(CI):5-10%]for HER2 status.Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17%(95%CI:7-29%) and 4%(95%CI:2-6%) respectively.No publication bias was found in the meta-analysis.Conclusions:The discordance of HER2 status is not rare in primary and metastatic GC through our metaanalysis.Prospective stuthes are needed to testify the clinical significance of the discordance of HER2 status.     

HER2 expression in gastric and oesophageal cancer: a meta-analytic review

Background

Since the advent and the success of adjuvant medical therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the form of trastuzumab there has been increasing interest in the development of similar therapies in other solid organ malignancies including gastric cancer and oesophageal cancer. Over the years, multiple observational studies have been inconsistent. Several meta-analyses have been published looking at the association between HER2 and gastric cancer and oesophageal cancer. This review aims to summarize the meta-analytic evidence for the association between HER2 in gastric and oesophageal cancer.

Methods

A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane Library, Google Scholar, Science Direct, and Web of Science.

Results

Of the articles selected, only nine studies met full criteria. Six of them reviewed the role of HER2 in gastric cancer and the remaining three reviewed its role in oesophageal cancer.

Conclusions

The current evidence regarding the role of HER2 is unclear. However, it clearly plays a key role in the pathogenesis of gastric and oesophageal carcinomas. Targeted therapy towards this subgroup (despite variable frequency and association with survival) would offer a mortality benefit and improve survival.     

HER2阳性乳腺癌治疗模式的进展和优化

随着抗人表皮生长因子受体2（human epidermalgrowth factor receptor 2 ,HER2）抗肿瘤药物的不断出现及广泛应用,HER2 阳性乳腺癌患者的治疗以及预后得到了显著的改善。PEONY 研究结果的发布再次奠定了帕妥珠单抗+曲妥珠单抗的双靶治疗模式在新辅助治疗领域中的地位;结合TRYPHAENA 和TRAIN-2 两项研究,紫杉类+铂类应该是抗HER2 双靶治疗的首选化疗方案,疗程宜6 个周期。结合中国乳腺癌新辅助治疗专家共识和辅助APT 研究的最新随访结果,新辅助治疗适用人群为肿瘤直径超过3 cm 和/或淋巴结阳性的患者,新辅助治疗后如果没有获得pCR,T-DM1 应该是辅助治疗的首选模式,帕妥珠单抗+曲妥珠单抗的双靶辅助模式期待PEONY 研究的后续生存随访;对于没有淋巴结转移的小肿瘤（≤3 cm）低危患者可以考虑免除新辅助治疗,采取直接手术+术后给予曲妥珠单抗联合单药紫杉醇的辅助治疗模式。曲妥珠单抗+帕妥珠单抗联合紫杉类药物依然是晚期HER2 阳性患者的标准一线治疗;对于中国患者而言,吡咯替尼联合卡培他滨可以作为二线的优选;T-DM1 可以作为三线及后线选择;曲妥珠单抗、帕妥珠单抗、T-DM1 治疗失败的情况下,DS-8201 成为新的选择模式;伴有脑转移的HER2 阳性晚期乳腺癌患者则可以考虑图卡替尼与曲妥珠单抗和卡培他滨的联合治疗模式。     

Efficacy generated by afatinib in a lung adenocarcinoma patient harboring HER2 S310Y mutation

Afatinib exhibits therapeutic efficacy for lung adenocarcinoma patients harboring HER2 exon 20 insertions. HER2 S310Y single site substitution was discovered in recent years and afatinib efficacy for adenocarcinoma patients harboring S310Y mutation has not been reported. We presented a case of a 41-year-old male patient with lung adenocarcinoma harboring the HER2 S310Y mutation obtained clinical response to the treatment of afatinib, an oral HER family blocker. After the treatment of afatinib, the patient achieved partial response (PR) in chest lesions and almost complete response (CR) in intracranial lesions. He experienced progressive disease (PD) with liver metastasis and achieved a progression-free survival (PFS) of 5 months. He continually treated with afatinib after CT guided percutaneous radiofrequency ablation to eradicate the hepatic tumor cells and achieved stable disease (SD). In this study, we reported the first clinical evidence of efficacy generated by afatinib, the irreversible HER family inhibitor, targeting HER2 S310Y single site mutation in lung adenocarcinoma.     

EGFR mutation status in primary lung adenocarcinomas and corresponding metastatic lesions: discordance in pleural metastases

Introduction

The aim of this study was to compare epidermal growth factor receptor (EGFR) and KRAS mutations between primary tumors and corresponding metastases including pleural metastases in lung adenocarcinoma.

Methods

Thirty-seven paired primary lung adenocarcinomas and corresponding metastatic tumors were analyzed for EGFR and KRAS mutations. In addition, 21 pleural metastases including malignant pleural effusion or pleural biopsy were used in performing these mutation analyses.

Results

EGFR mutations were detected in 18 primary lung adenocarcinomas (48.6%) and in 16 corresponding metastases (43.2%). EGFR mutations showed a discordance rate of 16.2% (6 of 37 patients) between primary lung adenocarcinomas and corresponding metastases. Among 21 pleural metastases, 3 patients (14.3%) showed that the EGFR mutation was discordant. KRAS mutations were detected in one primary tumor and in two metastatic tumors. Eighteen patients were treated with EGFR tyrosine kinase inhibitors. One of seven patients who experienced partial response had EGFR mutations only in the metastasis, and two of seven patients who experienced progressive disease carried wild-type EGFR only in the metastasis.

Conclusions

EGFR mutations were discordant between primary tumors and corresponding metastases in a significant portion of lung adenocarcinomas. Furthermore, these discordance was also observed in metastases to the pleura, the nearest metastatic site.     

HER2 status in lung adenocarcinoma: A comparison of immunohistochemistry,fluorescence in situ hybridization (FISH), dual-ISH,and gene mutations

Objectives

While novel anti-human epidermal growth factor receptor 2 (HER2) agents have recently been developed, no definite criteria have been proposed as indications for the use of these agents in patients with lung cancer. Here, we tested HER2 alterations by using four methods and explored the concordance of these methods to improve our understanding of the accuracy of HER2 testing methods.

Materials and methods

We analyzed HER2 protein expression by immunohistochemistry (IHC) and HER2 amplification by fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) by using a tissue microarray comprising lung adenocarcinoma specimens from 243 consecutive patients. The presence of mutations in the EGFR, KRAS, and HER2 genes were also determined.

Results

Positive IHC (score 3+) was observed in six cases (2.5%). Amplification of HER2 was observed in five cases (2.1%) by FISH and in nine cases (3.7%) by DISH. HER2 expression by IHC and gene amplification by FISH were significantly associated (P < 0.001). The overall concordance between FISH and DISH by amplification status was 96.7% (P < 0.001). One hundred nine tumors (49.9%) had EGFR mutations, 25 (11.2%) had KRAS mutations, and six (2.7%) had HER2 mutations. All of these mutations were mutually exclusive. Cases having HER2 mutations were positively correlated with cases having HER2 amplification (P < 0.001). Two of six cases with HER2 mutations showed amplifications by FISH and DISH tests.

Conclusion

HER2 protein overexpression, gene amplification, and gene mutations appeared to be uncommon in lung adenocarcinoma. Cases with HER2 mutations tended to show HER2 gene amplification. The results indicated that HER2 gene amplification and mutations should be tested to determine whether patients are eligible for administration of new anti-HER2 agents. In addition, DISH was better than FISH for detection of cases with HER2 amplification.