曲妥珠单抗原发耐药与继发耐药的研究进展

“曲妥珠单抗耐药”概念于2001年基于细胞系和动物模型的实验研究被首次提出,此后众多研究从不同的角度探索曲妥珠单抗耐药的分子机制。目前若干曲妥珠单抗耐药机制的研究已经单独针对原发耐药或继发耐药机制进行,本文对其研究结果进行综述。原发耐药与继发耐药机制的差异提示我们,在曲妥珠单抗治疗中应该根据不同的临床耐药患者亚群给予相应的临床治疗策略。     

Optimal sequence of implied modalities in the adjuvant setting of breast cancer treatment: an update on issues to consider

The adjuvant setting of early breast cancer treatment is an evolving field where different modalities must be combined to improve outcomes; moreover, quality of life of breast cancer survivors emerges as a new important parameter to consider, thus implying a better understanding of toxicities of these modalities. We have conducted a review focusing on the latest literature of the past 3 years, trying to evaluate the existing data on the maximum acceptable delay of radiotherapy when given as sole adjuvant treatment after surgery and the optimal sequence of all these modalities with respect to each other. It becomes evident radiotherapy should be given as soon as possible and within a time frame of 6-20 weeks. Chemotherapy is given before radiotherapy and hormone therapy. However, radiotherapy should be started within 7 months after surgery in these cases. Hormone therapy with tamoxifen might be given safely concomitantly or sequentially with radiotherapy although solid data are still lacking. The concurrent administration of letrozole and radiotherapy seems to be safe, whereas data on trastuzumab can imply only that it is safe to use concurrently with radiotherapy. Randomized comparisons of hormone therapy and trastuzumab administration with radiotherapy need to be performed.     

Efficacy of Trastuzumab in Routine Clinical Practice and After Progression for Metastatic Breast Cancer Patients: The Observational Hermine Study

Background.

The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP).

Patients and Methods.

The study observed 623 patients for ≥2 years. Treatment was given according to oncologists'' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for ≥30 days following progression or stopped at or before progression.

Results.

The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months).

Conclusion.

The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.     

Underuse of Anthracyclines in Women with HER‐2+ Advanced Breast Cancer

Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)‐2⁺ metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi‐institutional database containing the treatment history of 450 patients who received at least one trastuzumab‐based regimen for HER‐2⁺ metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline‐based therapy after failure with the first trastuzumab‐based regimen in eligible patients. Three‐hundred twenty‐one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab‐based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab‐based therapy for HER‐2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab‐refractory disease. A role for these compounds should be redefined in this patient subset.     

HER2阳性型乳腺癌脑转移的研究进展

近年来曲妥珠单抗的广泛应用大大提高了HER2（人表皮生长因子受体 2）过度表达乳腺癌患者的生存率,在全身性控制率提高和生存期延长的同时,脑转移瘤的发病率也有所增加;同时,脑转移是造成HER2阳性型乳腺癌晚期患者死亡的一项越来越重要的具有临床挑战性的因素——常常是在颅外疾病控制良好的情况下。本文将HER2阳性型乳腺癌脑转移的早期检测和预防的价值,靶向治疗的进展及新靶向药物的开发情况加以总结。     

Targeting receptor tyrosine kinases in gastric cancer

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials.One group of representative targeted oncogenic kinases,the receptor tyrosine kinases(RTKs),has been associated with gastric cancer development.Trastuzumab,an inhibitor of ERBB2,has been approved for the treatment of gastric cancer,although other receptor tyrosine kinases,such as epidermal growth factor receptor,vascular endothelial growth factor,platelet-derived growth factor receptor,c-Met,IGF-1R and fibroblast growth factor receptor 2,are also activated in gastric cancer.The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients.On the other hand,the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients;however,a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial.Other clinical trials,especially phaseⅢtrials that have tested drugs targeting RTKs,such as cetuximab,panitumumab,gefitinib,erlotinib,figitumumab,sorafenib,sunitinib and lapatinib,have shown that these drugs have modest effects against gastric cancer.This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.     

Neuregulin-1/erbB activities with focus on the susceptibility of the heart to anthracyclines

Neuregulin-1(NRG1)signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis,and it plays an essential role in maintaining the myocardial architecture during adulthood.The tyrosine kinase receptor erbB2 was first linked to the amplification and overexpression of erbb2 gene in a subtype of breast tumor cells,which is indicative of highly proliferative cells and likely a poor prognosis following conventional chemotherapy.The development of targeted therapies to block the survival of erbB2-positive cancer cells revealed that impaired NRG1 signaling through erbB2/erbB4 heterodimers combined with anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients.The ventricular-specific deletion of either erbb2 or erbb4 manifested dilated cardiomyopathy,which is aggravated by the administration of doxorubicin.Based on the exacerbated toxicity displayed by the combined treatment,it is expected that the relevant pathways would be affected in a synergistic manner.This review examines the NRG1 activities that were monitored in different model systems,focusing on the emerging pathways and molecular targets,which may aid in understanding the acquired dilated cardiomyopathy that occurs under the conditions of NRG1-deficient signaling.     

Targeting HER2 in ovarian and uterine cancers: Challenges and future directions

Targeting the human epidermal growth factor receptor 2 (HER2) has yielded major advances in breast cancer treatment. Accordingly, it has generated interest in targeting HER2 to treat gynecologic malignancies. Multiple studies have evaluated the rates of HER2 overexpression and/or amplification in ovarian and uterine cancers. HER2 has also been studied as a prognostic factor but resulting data has been contradictory. Moreover, clinical trials of HER2-directed therapies, including trastuzumab, pertuzumab, and lapatinib in ovarian and uterine cancers have been largely disappointing. Current research on HER2 in gynecologic malignancies has focused on identifying mechanisms of resistance and looking further into how HER2 signaling in gynecologic cancers differs from breast cancer. In this review, we highlight the existing data of targeting HER2 in ovarian and uterine carcinomas, many dating back more than a decade, and discuss future directions in pursuing HER2 as a potential target in these diseases.     

Immunohistochemical (IHC) HER-2/neu and Fluorescent-In–Situ Hybridization (FISH) Gene Amplification of Breast Cancer in Indian Women

Background: The concordance rate between immunohistochemical (IHC) and fluorescence in situ hybridization(FISH) results for HER2/neu according to clinical performance is controversial. The present prospective studywas theerefore conducted in Indian breast cancer patients. Methods: Fifty cases (n=50) of invasive duct cancerof breast tested for HER-2/neu by IHC and scored as 0, 1+, 2+ and 3+ by pathologists were further analyzed byFISH using a commercially available double-color probe, and the findings compared. Results: A total concordanceof 82.0% was observed with a Kappa coefficient of 0.640 (P < 0.001). A high discordance was observed in 30.0%of the patients with IHC 2+, 7.1% in IHC 3+, 19.2% overall in IHC 0 and 1+. Conclusion: IHC can be usedfirstly to screen the HER-2/neu status, and FISH can be used as a supplementary role to IHC and 2+ and somenegative cases. And only those cases with HER-2/neu status of IHC 3+ or FISH positive should be treated withHerceptin (Trastuzumab).