Role Of Trastuzumab Research Articles

Real-life analysis of neoadjuvant-therapy-associated benefits for pathological complete response and survival in early breast cancer patients - role of trastuzumab in HER2+ BC and platinum in TNBC.

Neoadjuvant therapy, which aims to achieve a pathological complete response (pCR) for better overall survival (OS) has several advantages for patients with early breast cancer (eBC) and subtypes of HER2-positive (HER2+) and triple-negative breast cancer (TNBC). However, there has been no large-scale real-world investigation on the clinical outcomes associated with trastuzumab-based and platinum-based neoadjuvant treatments for patients with HER2+ and TNBC, respectively. Taiwan Cancer Registry and National Health Insurance Research Database were utilized in this study. Patients diagnosed with clinically lymph-node-positive (LN+) HER2+ or TNBC were identified for analysis. Logistic regression and Cox proportional hazard models were employed to estimate the adjusted odds ratios (aOR) of achieving pCR and adjusted hazard ratios (aHR) of overall survival associated with treatment agents, respectively. A total of 1,178 HER2+ eBC and 354 early TNBC patients were identified, respectively. Neoadjuvant trastuzumab significantly increased the pCR rates by 3.87-fold among HER2+ patients. Trastuzumab-associated survival benefit was found in HER2+ patients who achieved pCR (aHR [95% CI]: 0.30 [0.11-0.84]) but not in those without pCR (1.13 [0.77-1.67]). Among the TNBC patients, platinum was associated with a 1.6-fold increased pCR rate; however, it did not improve OS regardless of pCR status. Trastuzumab improved pCR and OS for patients with HER2+ subtype. Using platinum agents for TNBC patients increased pCR rates but was not linked to better survival. Optimal neoadjuvant anti-HER2 therapy for patients with HER2+ eBC and the introduction of novel therapy for patients with TNBC should be considered.

The Role of Trastuzumab in Patients with HER2 Positive Small (pT1mi/a) Breast Cancers, a Multicenter Retrospective Study

Simple SummaryTreatment of small HER2+ breast cancers with adjuvant Trastuzumab is still controversial. This study aims to measure the effect of Trastuzumab in early stages of breast cancer (pT1mic/a pN0/1mi) in terms of disease recurrence and to identify which factors most affect the prognosis of small HER2+ tumors. We retrospectively selected and reviewed 100 HER2+ pT1mic-pT1a breast cancer patients with a median follow-up of 86 months. In our study the primary outcome was the disease recurrence rate, which appeared to be significantly lower among patients who received adjuvant Trastuzumab. Among the patients who did not receive adjuvant Trastuzumab, HR− HER2+ tumors showed a risk seven times higher of relapse. The results of our study indicate that adjuvant Trastuzumab reduces the risk of developing a disease recurrence even in small HER2+ tumors. Adjuvant targeted therapy should be considered in patients with HR− HER2+ tumors, the category with the highest risk of recurrence.The treatment with adjuvant Trastuzumab in patients diagnosed with HER2+ small breast cancers is controversial: limited prospective data from randomized trials is available. This study aims to measure the effect of Trastuzumab in the early stages of breast cancer (pT1mic/a pN0/1mi) in terms of disease recurrence and to identify which are the factors that most affect the prognosis of small HER2+ tumors. One hundred HER2+ pT1mic-pT1a breast cancer patients who were treated in three Turin Breast Units between January 1998 and December 2018 were retrospectively selected and reviewed. Trastuzumab was administered to 23 patients. Clinicopathological features and disease-free survival (DFS) were compared between different subgroups. The primary outcome was the disease recurrence rate. Median follow-up time was 86 months. Compared to pT1a tumors, pT1mic lesions had a higher tumor grade (84% of pT1mic vs. 55% of pT1a; p = 0.003), a higher Ki-67 index (81% vs. 46%; p = 0.007) and were more frequently hormone receptor (HR) negative (69% vs. 36%, p = 0.001). Disease recurrence rate was significantly lower among patients who received adjuvant Trastuzumab (p = 0.02), with this therapy conferring an 85% reduction in the risk of relapse (HR 0.15; p = 0.02). Among the patients who did not receive adjuvant Trastuzumab, the only factor significantly associated with an increased risk of developing a recurrence was the immunohistochemical (IHC) subtype: in fact, HR− HER2+ tumors showed a risk seven times higher of relapsing (HR 7.29; p = 0.003). Adjuvant Trastuzumab appears to reduce the risk of disease recurrence even in small HER2+ tumors. The adjuvant targeted therapy should be considered in patients with HR− HER2+ tumors since they have the highest risk of recurrence, independently from size and grade.

Immunohistochemical expression of HER-2/neu receptors in gastric carcinoma

Background/aim Gastric carcinoma is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related death. It is associated with patient morbidity and mortality worldwide. Adenocarcinomas represent 90% of gastric carcinoma cases and are classified into intestinal and diffuse types. Human epidermal growth factor receptor 2 (HER-2)/neu overexpression is a predictor of poor prognosis. This study aimed to evaluate HER-2/neu expression in gastric carcinomas and to correlate its expression with clinicopathological parameters and other prognostic factors. Patients and methods Forty-five cases of primary gastric carcinoma were included in this study. Thirty-two cases were of intestinal type and 13 cases were of the diffuse type. All specimens were formalin fixed, routinely processed, stained with hematoxylin and eosin, and immunohistochemically stained with HER-2/neu. Results Overexpression of HER-2/neu was detected in five out of 30 (11.1%) gastric carcinomas. There was a nonsignificant difference (P>0.05) in different histologic types. Also HER-2/neu expression showed a nonsignificant correlation with both histologic grade and tumor stage. Conclusion Our results revealed a limited effect of HER-2/neu on the biologic behavior of gastric carcinoma. However, further study with a larger sample size is recommended to clarify the therapeutic role of trastuzumab (Herceptin) in gastric carcinoma patients expressing HER-2/neu.

A Potential Additional Variable to Consider in the Surgical Treatment of Ductal Carcinoma in Situ.

HER2/neu is a potentially interesting variable that has been demonstrated to have a profound impact on the management of invasive breast carcinoma, and we performed this study to evaluate the differences between HER2-positive and HER2-negative ductal carcinoma in situ. The impetus for this study was our poor recruitment to the National Surgical Adjuvant Breast and Bowel Project Protocol B-43 trial that was designed to evaluate the potential role of trastuzumab in breast conservation therapy for patients with HER2-positive ductal carcinoma in situ. All patients with ductal carcinoma in situ and an assessment for the HER2/neu receptor were identified. Patients with HER2-positive and HER2-negative ductal carcinoma in situ were compared to determine differences in demographic, hormone receptor status, nuclear grade, presence of necrosis, surgical procedure (lumpectomy or mastectomy), tumor size, and extent of margins. Quantitative variables were analyzed with t test, and nominal variables were assessed by chi square analysis. A total of 177 patients were identified with a mean age of 61.0 years. A total of 101 patients (57.1%) were treated with lumpectomy, and 76 had mastectomy (42.9%). Forty-four (24.9%) patients were positive, and 133 (75.1%) were negative for the HER2/neu receptor. HER2-positive tumors were larger (23.6 vs 13.8 mm, P=0.001) and more likely to undergo mastectomy (61.4% vs 36.8%, P=0.01). Based on these results, an HER2-positive ductal carcinoma in situ is likely to be larger than an HER2-negative tumor, leading to more frequent use of mastectomy. This finding would explain our poor recruitment to the National Surgical Adjuvant Breast and Bowel Project Protocol B-43 trial.

Abstract 3921: A screen of breast and colon cancers with HER2 antibody clone UMAB36 does not exhibit the cross-reactivity of clone 4B5 with HER4 protein

Abstract Increased sensitivity and specificity of immunohistochemical (IHC) detection of HER2 expression is crucial as the role of Trastuzumab have expanded in the treatment of HER2 positive non-breast cancer patients such as gastric cancer patients. Non-specific nuclear and cytoplasmic staining of the HER2 antibody clone 4B5 has been reported by other labs. In this study, we evaluated the specificity of HER2 clone 4B5 and a new HER2 antibody clone UMAB36 using a suite of methods including protein lysate arrays, western blots, FISH and IHC correlation screens on 129 breast and 158 colon cancer cases for HER2 expression. The protein lysate array and western results revealed that clone 4B5 recognizes three proteins: HER2, HER4, and ZSCAN18, a nuclear transcription protein. In comparison, clone UMAB36 recognized only HER2 protein in the same protein lysate array and western screen as clone 4B5. False negative results, based on correlation of IHC with FISH HER2 positives, were generated using clone 4B5 in 1 breast and 5 gastric of the total 287 cancer cases screened. Comparatively, no false negative results were observed using clone UMAB36 in which there was a 100% correlation between IHC and FISH screen. In this study, areas of normal gastric tissue often stained positive by HER2 clone 4B5, so we performed further analysis of 470 normal gastric cases using Ventana's BenchMark instrument. The results show that 278 normal gastric cases had positive stain with clone 4B5 compared to 3 cases with clone UMAB36. The high background by clone 4B5 may be due HER4 being upregulated in adjacent normal gastric tissue. Our results indicate clone UMAB36 has higher specificity and sensitivity than clone 4B5 in screening gastric tumors. Citation Format: Lixin Zhou, Kehu Yuan, Fangfang Ren, Lili Ki, Min Zhou, Wei Fu, Xiaozheng Huang, Rachel M. Gonzalez, Youmin Shu, Yi Shen, Guangli Wang, Donghui Ma, Wei-Wu He, Jian Chen. A screen of breast and colon cancers with HER2 antibody clone UMAB36 does not exhibit the cross-reactivity of clone 4B5 with HER4 protein. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3921.

A Retrospective Study on the Efficacy of Trastuzumab in HER2-Positive and Tamoxifen-Refractory Breast Cancer with Brain Metastasis.

The role of trastuzumab in breast cancer with brain metastasis is still in discussion. This study was conducted to investigate the efficacy of trastuzumab in the management of human epidermal growth factor receptor 2 (HER2)-positive, tamoxifen-refractory breast cancer with brain metastasis. This retrospective study was conducted between January 2008 and December 2012. A total of 33 patients receiving trastuzumab treatment for HER2-positive, tamoxifen-refractory breast cancer with brain metastasis were assigned to the experimental group, while a matched group of 35 patients who received systemic therapy without trastuzumab were assigned to the control group. Data on the patient characteristics and clinical outcomes were collected and evaluated. Patients in the trastuzumab group showed a significantly better response to treatment than those in the control group (p = 0.025). Univariate and multivariate Cox proportional regression analyses indicated that progression-free survival was significantly longer in patients receiving trastuzumab therapy than in the control group (hazard ratio [HR] 2.213 [p = 0.003] and HR 3.056 [p < 0.001], respectively) and significantly shorter in patients with two or more extracranial metastases (HR 0.417 [p = 0.002] and HR 0.317 [p < 0.001], respectively). Furthermore, patients on trastuzumab treatment experienced longer overall survival than patients in the control group (HR 2.844 [p < 0.001] and HR 4.017 [p < 0.001], respectively), while shorter overall survival was seen in patients with two or more extracranial metastases (HR 0.524 [p = 0.021] and HR 0.430 [p = 0.005], respectively) and in those receiving capecitabine-based therapy as compared with anthracycline-based therapy (HR 0.558 [p = 0.030] and HR 0.449 [p = 0.011], respectively). Trastuzumab was found to benefit patients with HER2-positive, tamoxifen-refractory breast cancer with brain metastasis by improving progression-free and overall survival.

Abstract 2691: Role of trastuzumab in the combination treatment for a HER2-positive trastuzumab-resistant gastric cancer xenograft model

Abstract Objective: Trastuzumab (Tras) resistance is an important clinical problem to be resolved for HER2-positive gastric cancers (GC). Even after the tumor develops resistance to Tras, continuous anti-HER2 therapies, including Tras with chemotherapy (Tras beyond PD) or trastuzumab emtansine (T-DM1), could be effective treatment options. The Tras-sensitive cell line GLM-1 was established from a liver metastasis of a GC patient (Nakanishi et al. 2005), and the Tras-resistant cell line GLM1-HerR2 (R2) was established from GLM-1 by in vivo selection (Oshima et al. 2014). In this study, we used GLM1 and R2 xenograft models to examine the Tras-resistant mechanism of R2 and the effects of Tras plus paclitaxel (PTX) or T-DM1. Methods: BALB/c-nu/nu mice subcutaneously inoculated with GLM1 or R2 received Tras (40 mg/kg, qw) intraperitoneally, PTX (15 mg/kg, qw) or T-DM1 (10-40 mg/kg, q3w) intravenously (Day 1). Tumor volume (TV) was measured to evaluate antitumor effects, HercepTest® was used for HER2 status, and flow cytometry to analyze Tras-binding ability. Cell proliferation after knockdown of HER family receptors was measured by BrdU incorporation. Signal transduction was examined by Western blot for tumors excised on Days 2 and 5. Results: In contrast to GLM-1, R2 showed resistance to Tras treatment in xenograft experiments. There were no clear differences in HER2 score (3+), Tras-binding ability, p-HER2, p-HER3, p-AKT levels, or PIK3CA status (no hot spot mutation). Effects of gene knockdown of EGFR/HER2/HER3 in GLM-1 and R2 on cell proliferation were similar (ca. 10%/50%-60%/10% reduction, respectively). In GLM-1 tumors, Tras treatment decreased p-AKT, increased p27 protein, and decreased p-Rb, resulting in G1 cell cycle arrest, whereas in the R2 tumors changes in those molecules were few. These results suggest that escape from Tras-induced G1 arrest could be a resistant mechanism of R2. Based on the above results, and because in R2 cells HER2 remained a driver of proliferation and mitotic arrest was maintained, we hypothesized that Tras + PTX would show a higher antitumor effect than PTX alone. In the R2 xenograft model on Day 22, the Tras + PTX group showed a significantly higher antitumor activity (TV: 2 ± 3 mm3) than the PTX alone group (TV: 208 ± 209 mm3). In tumor specimens from the PTX and Tras + PTX groups, p-histon H3 (an M phase marker) was increased on Day 2. However, the Tras + PTX group, unlike the PTX group, showed markedly decreased p-histon H3 on Day 5, which suggests that Tras in combination with PTX enhances apoptosis in R2 tumors. Interestingly, T-DM1 showed dose-dependent antitumor activity in both GLM-1 and R2 xenografts. Conclusion: It was indicated that continuous anti-HER2 treatment, including Tras with chemotherapy or T-DM1 monotherapy, could be efficacious treatments for HER2-positive Tras-resistant GC tumors that emerge during previous Tras treatment. Citation Format: Sei Shu, Yoriko Yamashita-Kashima, Mieko Yanagisawa, Yoichiro Moriya, Naoki Harada. Role of trastuzumab in the combination treatment for a HER2-positive trastuzumab-resistant gastric cancer xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2691. doi:10.1158/1538-7445.AM2015-2691

Abstract P1-04-03: Prognostic and predictive implications of monosomy 17 in curable HER2-amplified breast cancer

Abstract Background: Monosomy of chromosome 17 is identified in approximately 6% of HER2-amplified breast cancers. Monosomy 17 has been retrospectively associated with inferior response to trastuzumab in the metastatic setting. The adverse impact of monosomy 17 could be related to the loss of putative genes encoding DNA-binding regulatory proteins, such as ROX or TOP2A. To date, the prognostic or predictive significance of monosomy 17 in women with potentially curable HER2-positive breast cancer has not been fully evaluated. Methods: Through a search of institutional databases, we identified women with HER2+ breast carcinoma with monosomy 17 by fluorescence in situ hybridization (FISH) and treated at our center between 1/1/00 and 6/1/11. HER2-amplification was defined as a HER2/CEP17 copy ratio ≥2.0, and monosomy 17 was defined as the presence of ≤1.4 CEP17 copies/cell. Clinical outcomes were determined by chart review, defined by Standardized Definitions for Efficacy (STEEP). Differences in treatment and other disease characteristics were compared by the log-rank test. Results: We identified 99 women with stage I-III HER2-positive breast cancer showing monosomy 17 by FISH: 51% (n=50) were treated with trastuzumab plus chemotherapy (tras/chemo), 31% (n=31) with chemotherapy (chemo alone), and 18% (n=18) with neither (no tras/chemo). An adjuvant anthracycline was administered in 82% of women in the tras/chemo group and 97% of women in the chemo group. The 3 treatment groups were balanced for age (median: tras/chemo 49y; chemo 53y; neither 56y), but were not balanced for hormone receptor (HR)-status (HR+: tras/chemo 96%; chemo 81%; neither 78%, p=0.04) or TNM stage (stage III: tras/chemo 16%; chemo 27%; neither 0%, p=0.01). With a median follow-up of 7y (0.16-13.4y), 4y distant relapse free survival (DRFS) was 100% for the tras/chemo group, 87% for the chemo alone group, and 80% for the no tras/chemo group (p=0.018); and 4y overall survival (OS) was 100% for the tras/chemo group, 93% for the chemo alone group, and 81% for the no tras/chemo group (p=0.005). Conclusions: Here we report the largest retrospective series of patients with curable HER2-amplified breast cancer and monosomy 17. HER2-amplified monosomy 17 does not appear to adversely affect survival in the curative setting, with outcomes comparable to those reported in large phase III adjuvant trastuzumab trials. Despite receiving less anthracycline-based chemotherapy, better OS and DRFS were observed in women treated with tras/chemo compared with women treated with chemo alone, thereby supporting the critical role of trastuzumab in this patient population, despite data to the contrary from the metastatic setting. Citation Format: David Page, Yong H Wen, Dana Dure, Clifford Hudis, Edi Brogi, Heather McArthur. Prognostic and predictive implications of monosomy 17 in curable HER2-amplified breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-03.

A critical review of HER2-positive gastric cancer evaluation and treatment: From trastuzumab, and beyond

Identification of the importance of human epidermal growth factor receptor-2 (HER2) status, biomarker testing and the development of anti-HER2 treatments have changed the prognosis of breast and gastric cancers. The addition of trastuzumab to chemotherapy has improved outcomes for patients with HER2-positive metastatic adenocarcinoma of the stomach and gastroesophageal junction, but some relevant issues remain to be elucidated or will emerge with new drugs. This article reviews the current state of HER2 in gastric cancer focusing on diagnostic and anti-HER2 targeted treatment issues and the role of trastuzumab in localized disease, and its combination or integration with new therapies.

Role of trastuzumab in infracentimetric HER2-positive breast cancer: The southern Italy experience.

e11512 Background: HER2 positive (HER2+) disease is relatively uncommon in early infracentimetric breast cancer (BC) accounting for approximately 10% of cases. Trastuzumab (T) based-adjuvant therap...

New therapeutic strategies for squamous cell cancer and adenocarcinoma

This paper presents commentaries on neoadjuvant treatment esophagectomy; the prognostic and predictive effects of single nucleotide polymorphisms (SNP) in the multimodality therapy of esophageal cancer; optimal preoperative treatment prior to surgery for esophageal cancer; a possible role for trastuzumab in treating esophageal adenocarcinoma or any esophageal dysplasia/intra-epithelial neoplasia; surgery after chemoradiation in resectable esophageal cancer; whether para-aortic lymph node dissection should be performed in esophagogastric junction (EGJ) tumors; and transhiatal esophagectomy in treatment of the esophageal cancer.

Targeting the Human Epidermal Growth Factor Receptor 2 in Esophageal Cancer

The importance of human epidermal growth factor-2 (HER2) in terms of prognosis and aggressiveness of growth has long been known in breast cancer, and interruption of its growth cascade by agents such as trastuzumab and lapatinib has markedly improved outcomes for these patients with HER2 overexpression. HER2 overexpression also occurs in many other tumor types, including esophageal cancer. In this disease, a different scoring system for determining overexpression is used. Limited data exist concerning the biological and therapeutic implications of HER2 overexpression in esophageal cancer. One trial, the so-called ToGA trial, included patients with advanced gastric and gastroesophageal junction (GEJ) tumors that overexpressed HER2. Patients who received trastuzumab plus cisplatin-based chemotherapy had more responses and longer progression-free and overall survival than those who received the chemotherapy alone. Enthusiasm concerning these results must be tempered by the facts that only 25% of the study group had GEJ tumors and, of these, only 33% had HER2 overexpression. Thus, the role of trastuzumab in the management of HER2-overexpressing esophageal cancers remains to be determined. In addition to presenting data on the HER2 cascade, the authors review clinical trials performed to date and also present the validated standard scoring system for HER2 overexpression in esophageal cancer.

P2-12-02: Correlation between BMI and Clinical Outcome of Patients with Early Stage HER2+ Breast Cancer from the N9831 Clinical Trial.

Abstract Background Obesity, as defined by body mass index (BMI), has been associated with increased recurrence rate, shorter DFS and increased death rates due to breast cancer (BC). Most of the studies to date have examined the relationship of BMI and DFS in patients with hormone receptor positive disease. To our knowledge, BMI and its relationship with outcome in early stage HER2 positive breast cancer has not previously been examined. The N9831 is a large phase III trial testing the role of trastuzumab in the adjuvant setting of high risk patients with early stage HER2+ BC. We hypothesized that the occurrence of overweight and obesity may correlate with outcome. Methods: This analysis presents BMI and its relation to tumor characteristics and DFS in patients (pts) enrolled in the N9831 clinical trial. Pts were categorized as normal weight, overweight or obese using the WHO BMI classification parameters of &amp;lt; 25%, 25–29% and ≥ 30% respectively. For patient characteristics, patients were grouped into non-obese (BMI&amp;lt; 30) and obese (≥ 30) cohorts. DFS was estimated by the Kaplan-Meier method. Comparisons between arms A (chemotherapy alone), B (chemotherapy plus sequential trastuzumab) and C (chemotherapy plus concurrent trastuzumab) were performed using the Cox proportional hazards model, stratified by BMI. Results: Analysis was completed on 3,017 eligible pts. Obese pts were more likely to be older and postmenopausal (p&amp;lt;0.0001 for both). There was no significant association between BMI and ER/PR status (p=0.07) or histologic tumor grade (p=0.33). Obese pts were found to have significantly larger tumors ≥ 2 cm (p=0.002) and more positive lymph nodes (p=0.02). There was no significant difference in DFS within each intrinsic arm (A, B and C) between the obese and non-obese pts at 3, 5 or 7 yrs of follow up. However, pts in the non-obese group had significantly improved DFS in arm B and C compared to arm A (p=0.001 and p&amp;lt;0.0001 respectively). Also obese pts in arm C had significantly improved DFS compared to obese pts in arm A (p=0.008). There was a trend of improved DFS in the obese group in arm B compared to arm A, but this was not statistically significant (p=0.09). Pts in the normal weight and overweight groups did significantly better in arm B (p=0.02 for both) and arm C (p=0.01 and p=0.002 respectively) compared to arm A. Conclusions: This analysis of data from the N9831 study confirms that obese pts with early stage HER2+ tumors have worse clinical outcome than pts with BMI &amp;lt; 30%. Adjuvant trastuzumab improved clinical outcome regardless of BMI. This study supports weight loss intervention for obese women with early stage HER2+ BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-02.

Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight

Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight

Role of trastuzumab in the management of HER2-positive metastatic breast cancer

Breast cancer is a major health issue in developed countries. Overexpression of HER2, a member of epidermal growth factor receptor family, occurs in 20%-30% of breast cancers. HER2 drives the cancer cells to develop a more aggressive phenotype, to metastasize to viscera and central nervous system, and to be less sensitive to chemotherapeutic agents. Trastuzumab (Herceptin®) is a monoclonal antibody directed against the extracellular domain of HER2. As single agent or with chemotherapy, trastuzumab improves survival of HER2-positive breast cancers. In the past years, trastuzumab has completely revolutionized the scenario of the treatment of HER2-positive breast cancer, representing one of the most remarkable examples of targeted therapy in oncology. However, issues such as the best chemotherapeutic companion to associate with trastuzumab, cardiac toxicities, and clinical resistance still require tremendous efforts by researchers. Here, we review pharmacology, efficacy studies, and toxicities of trastuzumab in metastatic breast cancer. Moreover, we provide some insights on resistance to therapy. Finally, we briefly discuss trastuzumab's place in the clinical setting.

Pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen in gastric cancer: a case report

We report a 49-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen. He underwent esophagogastroduodenoscopy in September 2009, which revealed a 2-cm gastric ulcer on the lesser curvature proximal to angularis. Biopsy of gastric ulcer showed moderately differentiated adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and fluorescence in situ hybridization. Further workups with endoscopic ultrasound, computed tomography and positron emission tomography staged his cancer as T3N1M0. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, docetaxel and capecitabine without severe toxicities except grade 2 diarrhea near the completion of cycle 3 requiring discontinuation of capecitabine. Afterwards, he received total gastrectomy with extended D2 lymph node dissections showing pathological complete response. He went on to receive 3 more cycles of chemotherapy postoperatively. The role of trastuzumab as a part of perioperative therapy in gastric cancer overexpressing HER2 is worth further investigation.

The role of trastuzumab in the management of HER2-positive metastatic breast cancer: an updated review

Currently, trastuzumab is one of the key drugs in the treatment strategy for HER2-positive breast cancer. Although metastatic breast cancer is unlikely to be cured, some HER2-positive patients have survived for a long time with complete response to trastuzumab therapy. In HER2-positive metastatic breast cancer, single agent trastuzumab is effective and less toxic. Combination of trastuzumab with cytotoxic drugs is also effective. Therefore, major guidelines recommend using trastuzumab as a key drug in the management of HER2-positive metastatic breast cancer. However, many clinical questions still need to be solved. In this article, recent evidence was reviewed to find some answers about these issues.

Role of Trastuzumab in the Adjuvant Treatment of HER2-Positive Early Breast Cancer

Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18-23% of invasive breast carcinomas and is associated with a worse prognosis. This novel transforming gene was identified in 1985, and in 1987 HER2 amplification was demonstrated to be central to the aggressive, malignant phenotype of these cancers and a significant predictor of both time to relapse and overall survival. These observations led to the development of the first monoclonal antibody targeting the extracellular domain of HER2, trastuzumab (Herceptin, Genentech and Hoffman LaRoche, Switzerland), which was approved by the US FDA for metastatic breast cancer in 1998. In 2005, results from four major trastuzumab adjuvant trials demonstrated a marked reduction in risk of recurrence, and trastuzumab is now an essential component of the adjuvant treatment of HER2-positive early breast cancer. Concerns regarding cardiac safety and mechanisms of resistance to trastuzumab remain important issues and are being addressed in ongoing research efforts.

Phase II trial of neoadjuvant chemotherapy of sequential FEC100 followed by docetaxel, carboplatin and trastuzumab (TCH) for HER-2 over-expressing locally advanced breast cancer (LABC): a multi-centre study from British Columbia.

Abstract Abstract #5118 Background: The role of trastuzumab either concurrent or sequential with adjuvant chemotherapy have clearly demonstrated significant benefits in early stage HER-2 positive breast cancer. There is now an accumulation of phase II and III trials also demonstrating improved pathological complete responses (pCR) in HER-2 positive breast cancer with neoadjuvant trastuzumab concurrent with chemotherapy. The number of patients on these trials are significantly fewer, and many of these trials are a mixture of primary operable and LABC. We have completed a multi-centre phase II trial of neoadjuvant chemotherapy and trastuzumab in HER-2 positive LABC.&amp;#x2028; Methods: Women with HER-2 positive (IHC 3+ or FISH+) stage IIB-IIIC breast cancer were enrolled. Treatment consisted of 4 cycles of FEC100 (5-FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) followed by 4 cycles of TCH (Docetaxel 75 mg/m2, carboplatin AUC 6, trastuzumab 8 mg/kg loading then 6 mg/kg q3 weekly). Trastuzumab was also continued adjuvantly for 9 months following chemotherapy and surgery. Cardiac monitoring every 3 months was mandated. A correlative translational component with baseline and interval biopsies and serum collection was also performed.&amp;#x2028; Results: A total of 30 patients (3 stage IIB; 14 IIIA; 10 IIIB and 3 IIIC) over a 3 year time period in 4 centres were accrued. Median age was 49 years (26-77 years). 60% of tumours were ER negative. There was one clinical CHF and 2 asymptomatic falls in LVEF requiring early discontinuation of trastuzumab. There were 3 episodes (10%) of febrile neutropenia. Seven patients underwent adjuvant radiotherapy prior to surgery. The pCR rate (breast and axilla) for the entire study population was 60% (18/30). There have been 3 recurrences so far (all biopsy proven) – of which 2 were brain metastases only. Further details on toxicity and changes in LVEF will be presented.&amp;#x2028; Conclusions: This multi-centre phase II trial clearly demonstrates significant activity (pCR 60%) for neoadjuvant anthracyclines followed by concurrent taxane, platinum and trastuzumab in a HER-2 positive LABC population. Overall the treatment regimen was well tolerated. Brain metastases however appear to be a common site of relapse in this high risk patient population and further treatment strategies directed at this site should be investigated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5118.

The role of trastuzumab in the adjuvant setting

The role of trastuzumab in the adjuvant setting