HER2 therapies and gastric cancer:A step forward

Gastric cancer usually is diagnosed in advanced stages and thus current medical practice affords limited therapeutic options.However,recent studies established the role of human epidermal growth factor receptor 2(HER2)in clinical management.Trastuzumab,an antiHER2 monoclonal antibody,acquired a main role in advanced gastric cancer harboring HER2 overexpression and/or amplification improving survival to 17.1 mo according to trastuzumab for gastric cancer phaseⅢtrial results.Also,new promising drugs,such as c-Met inhibitors,are in development and assessment for this setting.Certainly,novel drugs will emerge in the next feel years for help oncologists improve clinical management of advanced gastric cancer providing higher survival and quality of life.In this mini-review we will discuss some issues in this regard and provide an actual overview of this setting.     

Therapy of metastatic breast cancer with humanized antibodies against the HER2 receptor protein

The HER2 protein, a member of the epidermal growth factor family, is encoded by the protooncogene c-erbB-2. Its overexpression, occurring in approximately one-third of all breast carcinomas, is associated with a poor prognosis. A humanized mouse antibody against HER2 has been developed by genetic engineering. Here an unspecific human IgG was connected to the recognizing mouse IgG fragment. The allergization typical for allogeneic antibodies does not take place in this context. The effectiveness of this antibody has been confirmed by two international prospective phase III trials that tested it alone and combined with chemotherapy. Both modes of application increased the response rates and the time to progression. Side-effects were rare except for a high rate of cardiac dysfunction when the antibody was combined with anthracyclines. The effectiveness and negligible side-effects of the chimeric antibody against HER2 (Herceptin) render it a valuable tool in the treatment of breast cancer. Received: 8 February 1999 / Accepted: 6 April 1999     

Pathologic complete response to neoadjuvant anti-HER2 therapy is associated with HER2 immunohistochemistry score in HER2-positive early breast cancer

To evaluate whether pathologic complete response (pCR) to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapy is dependent on the HER2 immunohistochemistry (IHC) score.A total of 181 HER2-positive early breast cancer patients who had received neoadjuvant anti-HER2 therapy were included in this study. Associations were examined between IHC score and tumor pCR status (commonly defined by ypT0+ypN0, ypT0/is+ypN0, or ypT0/is).In trastuzumab-based neoadjuvant-treated patients, ypT0+ypN0 was achieved in 46.0% of patients with HER2 IHC 3+ tumors but only 25.0% of patients with HER2 IHC 2+/fluorescence in situ hybridization (FISH)-positive tumors (P = .016). When pCR was defined as ypT0/is+ypN0 or ypT0/is, 54.7% and 61.3% of patients with HER2 IHC 3+ tumors had a pCR, whereas only 29.5% and 38.6% with HER2 IHC 2+/FISH-positive tumors achieved pCR (P = .004 and P = .008, respectively). The association between dual HER2 blockade and pCR was almost exclusively confined to HER2 IHC 3+ tumors (ypT0+ypN0: 61.9% vs 38.9%, P = .013; ypT0/is+ypN0: 71.4% vs 47.4%, P = .009; and ypT0/is: 81.0% vs 52.6%, P = .002) and was absent in HER2 IHC 2+/FISH-positive tumors. Multivariate logistic regression revealed that HER2 IHC 3+ tumors had a significantly higher probability of achieving ypT0+ypN0 (odds ratio [OR], 0.265; 95% confidence interval [CI], 0.109–0.645; P = .003), ypT0/is+ypN0 (OR, 0.221; 95% CI, 0.094–0.521; P = .001), and ypT0/is (OR, 0.254; 95% CI, 0.111–0.583; P = .001) than HER2 IHC 2+/FISH-positive tumors. A significantly better pCR rate was also found in patients with T1 tumors and patients with dual HER2 blockade.The pCR rate was highly correlated with the HER2 IHC score in neoadjuvant anti-HER2 treatment. The addition of pertuzumab to a neoadjuvant trastuzumab-based regimen improved pCR rates, but there was no significant difference in pCR rates in the IHC 2+/FISH-positive group. This suggests that HER2 IHC scores can predict the effectiveness of treatment.     

Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells

We analyzed the cross-talk between receptors for vasoactive intestinal peptide (VIP) and the human epidermal growth factor family of tyrosine kinase receptors (HER) in oestrogen-dependent (T47D) and oestrogen-independent (MDA-MB-468) human breast cancer cells. VIP treatment slowly increased the expression levels of EGFR but it rapidly augmented phosphorylation of EGFR and HER2 in both cell lines. This pattern of HERs transactivation was blocked by the specific VIP antagonist JV-1-53, supporting the direct involvement of VIP receptors in formation of P-EGFR and P-HER2. VIP-induced transactivation was also abolished by H89 (protein kinase A inhibitor), PP2 (Src inhibitor) or TAPI-1 (inhibitor of matrix metalloproteases), following a differential pattern. These results shed a new light on the specific signalling pathways involved in EGFR/HER2 transactivation by VPAC receptors and suggest the potential usefulness of VIP receptor antagonists together with current antibodies against EGFR/HER2 and/or tyrosine kinase inhibitors for breast cancer therapy.     

HER2 overexpression and activation, and tamoxifen efficacy in receptor-positive early breast cancer

Objectives  Tamoxifen is a partial ER antagonist that is highly effective in the treatment of receptor positive breast cancer. It significantly reduces recurrence and improves survival in both pre- and postmenopausal women. Unfortunately, many ER+ positive tumors progress despite tamoxifen treatment and until now, no possibility exists to prospectively identify tamoxifen-resistant tumors. It has been suggested that that in HER2 over-expressing tumors, cross-talk via activated HER2 receptors is a key mechanisms by which tumors become tamoxifen-resistant. Methods  We have therefore used immunohistochemistry to analyze the expression of HER2 and activated ptyr-1248 HER2 in 408 women of ER+, early breast cancer who had received at least 2 years of adjuvant tamoxifen. We then analyzed possible associations between HER2 and pHER2 expression, and prognostic parameters, and evaluated the effect of HER2 expression and survival. Results  With HER2 being positive in 12 of 208 (2.9%) of ER+ positive tumors, HER2 overexpression was found to be considerably less common in ER+ tumors than what has been thought previously. The majority of HER2 overexpressing tumors, however, also expressed the activated receptor form (r = 0.664; P < 0.0001). Both HER2 and pHER2 are moderately correlated with Grading (r = 0.138; P = 0.0052 and r = 0.118; P = 0.0241, respectively) and nodal involvement (r = 0.163; P = 0.0018 and r = 0.134; P = 0.016, respectively), but neither HER2 nor its activated form are significant predictors of RFS, DFS, or OS. Conclusions  Taken together, we have demonstrated that in ER+ breast cancer, the HER2 receptor is commonly activated, but its low prevalence in ER+ tumors does not render it a useful prognostic parameter in tamoxifen-treated patients.     

Characterization of PI3KCA and BRAF mutations in gastric adenocarcinoma: An approach to a personalized targeted therapy for Moroccan HER2 overexpressed patients

Background and study aims

Targeted therapies have an increasing importance in digestive oncology. To our knowledge, we are the first to report the distribution of PI3KCA and BRAF mutations in Moroccan HER2 overexpressed patients, in order to introduce targeted therapy in the arsenal of therapeutic modalities for management in Morocco.

Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment

Background

In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse.

Method

In this study, CETC were monitored using the Maintrac^® method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib.

Results

In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease.

Conclusions

In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

     

Antitumor activity of the HER2 dimerization inhibitor pertuzumab on human colon cancer cells in vitro and in vivo

Purpose  The monoclonal antibody pertuzumab represents the first HER2 dimerization inhibitor with unknown activity in colon cancer treatment. We examined the antitumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in vitro and in vivo. Methods  Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis. The effect of pertuzumab on cell cycle distribution was analyzed by FACS. Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib. Tumor volume was measured repeatedly. Tumor histology was analyzed for necrosis. Results  Six of nine cell lines showed high expression of HER1/HER2. Pertuzumab inhibited cell cycle progression in various cell lines. Pertuzumab showed minor antitumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib (P < 0.001). Combination of pertuzumab with irinotecan had no additional effect on growth of additional tumors. Pertuzumab treated DLD-1 xenograft tumors did not show enhanced necrosis, which, however, was found in HCT116 derived xenografts. Conclusions  Pertuzumab has some antitumor activity on human colon cancer cells in vitro and in vivo, in particular when combined with erlotinib. In vivo, pertuzumab combination treatment was not superior to irinotecan monotherapy. These data warrant further investigation of simultaneous HER1/EGFR TKI inhibition and HER1/HER2 dimerization inhibition for colorectal cancer therapy.     

Prevalence and management of HER2/neu-positive early breast cancer in a single institution following availability of adjuvant trastuzumab

Aim: To ascertain the prevalence of HER2/neu‐positive early breast cancer (EBC), utilisation of adjuvant trastuzumab and incidence of cardiac toxicity in a community private hospital setting. Methods: Prospective data collected by breast oncologist and surgeons in all women diagnosed with EBC at the Mount Hospital (MH) were reviewed. Women with HER2/neu‐positive disease diagnosed between 1 October 2006 and 31 March 2009 were included in this analysis. Results: In total, 1128 women with invasive EBC were seen in the 30‐month period. All tumours underwent HER2/neu testing by immunohistochemistry, with 61% being evaluated by in situ hybridisation. Time to definitive HER2/neu result improved over time from median of 17 to 14 days. The prevalence of HER2 positivity (by in situ hybridisation) in this cohort was 12%. Uptake of trastuzumab‐based treatment was 100% in those patients receiving their treatment at the MH, compared to 52% of the 25 patients treated elsewhere. Ninety‐eight per cent of MH patients completed the planned 12 months of therapy, with one patient developing recurrent disease and two patients experiencing significant cardiac toxicity. Chemotherapy relative dose intensity was 98% in HER2/neu‐positive and negative patients. At a median of 25 months follow up, actuarial disease‐free and overall survival in the HER2/neu‐positive cohort is 99% and 100% respectively. Conclusion: In a community private hospital setting, adjuvant trastuzumab and chemotherapy was delivered optimally, in line with national and international guidelines. Early efficacy and safety results in a non‐clinical trial setting underscore the significant benefits achieved with this targeted therapy in HER2/neu‐positive EBC.     

HER2／neu在胃癌中的研究进展

HER2/neu与多种肿瘤的发生、发展关系密切。它通过下游的信号转导途径参与肿瘤细胞的增殖、凋亡、浸润与侵袭等基因的调控。HER2/neu在胃癌中存在高表达或基因扩增现象,并可能影响胃癌患者的预后,也可能参与了胃癌肝转移过程。HER2/neu有望成为胃癌治疗的一个新靶点。     

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer.Plasma membrane calcium ATPases (PMCAs) are a family of ion pumps that transport calcium out of cells and maintain low resting intracellular calcium levels (1–3). PMCA2 (gene symbol Atp2b2) is highly expressed in the apical membrane of mammary epithelial cells only during lactation, where it has been shown to transport calcium into milk (4–6). After weaning, PMCA2 expression rapidly decreases, contributing to the initiation of programmed cell death and mammary gland involution (7, 8). PMCA2 is also expressed in breast cancers (8–10), and high levels of tumor PMCA2 expression predict increased mortality in patients (8).Approximately 25–30% of invasive breast cancers overexpress human epidermal growth factor receptor 2 (HER2) as a result of amplification of the ERBB2 kinase gene (11–13), and overexpression of HER2 causes breast tumors in mouse mammary tumor virus (MMTV)-Neu transgenic mice (14). HER2 functions as a heterodimer with other ERBB family members, most commonly pairing with EGFR or human epidermal growth factor receptor 3 (HER3) in breast cancers (11, 13). For reasons that remain poorly understood, in contrast to other ERBB family members, which are internalized and degraded after stimulation, HER2 remains on the cell surface and continues to signal for prolonged periods (12, 15).In this study, we describe a previously unrecognized function for PMCA2: supporting active HER2 signaling and HER2-mediated tumor formation. Our data suggest that PMCA2 interacts with HER2 within specific membrane domains and is required for HER2 expression, membrane retention, and signaling.     

RNA interference-directed silencing of VPAC1 receptor inhibits VIP effects on both EGFR and HER2 transactivation and VEGF secretion in human breast cancer cells

We used small-interference RNA (siRNA) to explore the mechanisms of some vasoactive intestinal peptide (VIP) actions on human breast cancer cells. Transfection of estrogen-dependent (T47D) and estrogen-independent (MDA-MB-468) breast cancer cells with VPAC₁-receptor siRNA completely abolished VIP stimulatory effect on secretion of the main angiogenic factor, vascular endothelial growth factor (VEGF), and transactivation of epidermal growth factor receptor (EGFR or HER1) and HER2, two members of HER family of tyrosine-kinase receptors. The silencing procedure suggested the involvement of EGFR and HER2 transactivation in VIP-stimulated VEGF secretion. It was further supported by blocking tyrosine kinase activity by the selective HER inhibitors AG-1478 (EGFR) and AG-825 (HER2). Results give value to the specific signaling of VIP through VPAC₁ receptor in human breast cancer cells and support the potential use of VPAC₁-receptor antagonists in combined targeted therapies for breast cancer. Molecular therapies involving RNA interference of VPAC₁-receptor expression could also be considered.     

HER2与胃癌的研究进展

本文综述了HER2与胃癌相关的研究进展,介绍了HER2的结构、相关信号途径、在胃癌中的检测方法和检出率以及人源化抗HER2单克隆抗体曲妥珠单抗与胃癌治疗、HER2与胃癌预后的关系。研究显示HER2阳性是胃癌预后不良的重要因子,曲妥珠单抗与化疗药物联合应用是HER2阳性进展期胃和胃食管连接部癌以及伴肝转移患者治疗的新选择,可明显改善患者预后。     

Clinical therapeutic effects of trastuzumab in HER2-positive breast cancer patients: A protocol for systematic review and meta-analysis

Background:Despite the developments in diagnosis and treatment of HER2-positive metastatic breast cancer, there is a high likelihood in the development of resistance to trastuzumab. In general, HER2-positive patients with deteriorated health face negative clinical outcomes. The present study is conducted to systematically explore the medicinal properties of trastuzumab in HER2-positive breast cancer patients.Methods:Randomized controlled trials investigating the clinical properties of including trastuzumab to treat HER2-positive breast cancer cases will be sourced by exploring these online-based databases: MEDLINE, BIOSIS, China National Knowledge Infrastructure (CNKI), Cochrane Library, EMBASE, Central Register of Controlled Trials, and WanFang. Two independent authors will screen the literature, gather data, and assess the quality of selected studies. The significance of the relationship between the medical properties of trastuzumab when incorporated to treat HER2-positive breast cancer cases will be evaluated according to the relative risk, mean differences or standardized mean differences, and 95% confidence interval.Results:The outcomes from this review shall be issued in a journal that will be reviewed by peers.Conclusion:The conclusions presented in this review will serve as a reference for clinical practitioners and scholars to determine whether trastuzumab is an effective and safety intervention for treating HER2-positive breast cancer patients.Ethics and dissemination:Since this study is a systematic review of published studies, an ethical approval is not needed.Systematic review registration number:March 31, 2021.osf.io/wvqkf (https://osf.io/wvqkf/).     

HER2 testing in gastric cancer: An update

Human epidermal growth factor receptor 2(HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system.     

Preoperative therapy with epidoxorubicin and docetaxel plus trastuzumab in patients with primary breast cancer: a pilot study

Purpose Combining anthracyclines and taxanes are to date the most active cytotoxic treatment option in the neoadjuvant and palliative therapy of breast cancer patients. Adding trastuzumab to these cytotoxic agents can improve outcome for women with human epidermal growth factor receptor 2 (HER2)-overexpressing advanced breast cancer. We conducted a pilot study of preoperative epidoxorubicin and docetaxel plus trastuzumab in outpatient patients suffering from breast cancer.Patients and methods Fourteen consecutive patients were enrolled in this prospective clinical pilot trial. Preoperative treatment consisted of weekly trastuzumab (4 mg/kg body-weight loading dose, 2 mg/kg/week maintenance dose), in combination with weekly epidoxorubicin (30 mg/m² body surface area [BSA]) and docetaxel (35 mg/m² BSA) once a week for 6 weeks followed by 1 week off therapy.Results Patients received a total of 30 cycles (median: 2 cycles, range: 2–3 cycles) of this therapeutic regimen. Outpatient epidoxorubicin and docetaxel plus trastuzumab were well tolerated. A major response to this preoperative therapy regimen could be demonstrated in 12 of 14 patients (86%) leading to breast-conserving surgery in 11 of 14 patients (79%).Conclusions We conclude that outpatient epidoxorubicin and docetaxel plus trastuzumab are safe in the neoadjuvant treatment of patients suffering from breast cancer, based on a favorable side-effect and activity profile. Thus, this regimen can be considered for further clinical trials.Work under the Auspices of CLEXO (Center of Excellence for Clinical and Experimental Oncology)     

Dynamic changes in intrinsic subtype,immunity status,and risk score before and after neoadjuvant chemo- and HER2-targeted therapy without pCR in HER2-positive breast cancers: A cross-sectional analysis

Very few studies have been done in HER2 positive patients without complete pathological response (pCR) after combined neoadjuvant chemo- and HER2-target therapy to investigate changes in intrinsic subtype, risk of recurrence (ROR) score, and immunity status before and after treatment.Patients with nonmetastatic HER2-positive breast cancer failed to achieve pCR after neoadjuvant chemotherapy plus trastuzumab were included in current study. We examined the distribution of PAM50 subtypes, ROR score and immunity score in 25 paired baseline and surgical samples. The Miller–Payne grading system was used to evaluate the efficacy of the neoadjuvant therapy. It was observed that the distribution of intrinsic subtype, ROR category and immunity subgroup varied according to hormone receptor (HR) status. HER2-enriched and basal-like subtypes, median-high ROR categories and immunity-weak subgroup were dominant in baseline tumors. Compared to baseline samples, conversion of intrinsic subtype, ROR categories and immunity subgroups were found in 15 (60.0%), 13(52.0%), and 11(44.0%) surgical samples, respectively. The PAM50 subtype, ROR category, and immunity subgroup were concordant between baseline and surgical samples where nonluminal subtypes, median-high ROR categories and i-weak subgroup were still common.In conclusion, the HER2-positive breast cancer is highly heterogeneous with a distribution of 72-gene expression varying according to HR co-expression. The dynamics of the 72-gene expression pre- and posttreatment may become novel biomarker for guiding adjuvant therapy and hence warrant further investigation.     

Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

Globally,gastric cancer is the 4thmost frequently diagnosed cancer and the 2ndleading cause of death from cancer,with an estimated 990000 new cases and738000 deaths registered in 2008.In the advanced setting,standard chemotherapies protocols acquired an important role since last decades in prolong survival.Moreover,recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2(HER2)therapies.Trastuzumab,an anti-HER2 monoclonal antibody,was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy.Further,HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field.Thus,we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer,providing a comprehensive overview of molecular mechanisms and novel trials involved.