A case of metastatic Breast Cancer with HER2 gene amplification that responded completely to single agent trastuzumab

An 80-year-old woman visited our hospital with a massive ulcerated tumor in the upper lateral quadrant of the right breast. Her performance status was 2. Histopathologically, a mass consisting of a huge primary tumor and metastatic axillary lymph nodes was seen and invasive ductal carcinoma was diagnosed. Both estrogen and progesterone receptors were negative. Herceptest (DakoCytomation, Glostrup, Denmark) showed 2 + staining and HER2 amplification was detected by fluorescent in situ hybridization. CT revealed multiple lung metastases. Her old age and performance status of 2 made aggressive chemotherapy difficult. After receiving 5'-DFUR 600 mg/day as the first line treatment for two months, the tumors progressed. As second-line treatment, single agent therapy with a loading dose, a trastuzumab 4 mg/kg followed by 2 mg/kg weekly was recommended. The patient also received 60 Gy radiotherapy. Six months after the second line treatment, the breast tumor disappeared and only a scar remained on the chest wall and axilla. CT showed no lung tumors. During the trastuzumab treatment, no adverse effect was observed. Her performance status improved to zero, and she is alive and free from the disease 24 months after the disappearance of the tumor.     

A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution

Recently published clinical trial data have produced compelling evidence for increased survival when Herceptin is administered to patients whose tumors are HER2 amplified. Therefore, the accuracy of HER2 status is essential to determine which patients should or should not receive Herceptin. Although HER2 results obtained by FISH and IHC are often in agreement, there is a persistent group of cases in which results are discordant, particularly among tumors with intermediate results. A multivariable analysis was undertaken to determine relative significance of various clinical and pathologic findings for patients diagnosed with infiltrating ductal carcinoma, and a data model was produced that predicts which patients are most likely to have HER2 amplified tumors. Correlates of HER2 amplification were higher Scarff-Bloom-Richardson grade, younger age at diagnosis, and a comedo ductal carcinoma in situ component.     

Parotid Gland Metastasis of Breast Cancer: Case Report and Review of the Literature

BACKGROUND: Parotid gland metastasis in breast cancer is extremely rare, and only 14 cases have been reported between 1982 and 2010. CASE REPORT: A 67-year-old female patient was diagnosed with invasive lobular carcinoma of the left breast. Although clinical staging was T1N3M1 (stage IV), the tumor experienced a complete response to chemotherapy. We therefore performed a mastectomy followed by radiotherapy, and continued administration of trastuzumab. However, 11 months later, the patient complained of a swelling in the left parotid gland. Histology following a partial parotidectomy revealed a parotid gland metastasis from the breast. CONCLUSION: Treatment with capecitabine in addition to trastuzumab, which is one of the strategies applied in HER2-positive breast cancer, was effective in our patient. Analysis of the 14 cases of parotid gland metastasis from the breast reported between 1982 and 2010 revealed that the metastasis may occur not by direct lymphatic but by hematogenous spread.     

Optimal timing for adjuvant radiation therapy in breast cancer: A comprehensive review and perspectives

Purpose

The optimal sequence of modalities involved in breast cancer treatment with respect to radiotherapy and the maximum acceptable interval between radiotherapy and surgery need to be determined.

Design

This review attempts a critical reading of the literature.

Results

A delay of radiotherapy more than 8-12 weeks after surgery adversely affects local recurrence. Radiotherapy should be administered within 7 months after surgery, when chemotherapy is administered first. Several chemotherapy regimens can be safely administered concurrently with radiotherapy. The concurrent use of tamoxifen with chemotherapy should be avoided, but not with radiotherapy. Data is insufficient with regard to concurrent use of aromatase inhibitors with radiotherapy. The use of trastuzumab concomitantly with radiotherapy may enhance toxicities but may also improve its efficacy.

Conclusions

Although the issue of radiotherapy delay and that of sequence with chemotherapy or tamoxifen are clarified, the sequence of radiotherapy with aromatase inhibitors and trastuzumab needs to be defined. Individual radiosensitivity may influence toxicity. New biologic markers have to be determined in the future for tailoring radiotherapy in breast cancer.     

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.

     

The predictive role of phosphatase and tensin homolog (PTEN) loss,phosphoinositol-3 (PI3) kinase (PIK3CA) mutation,and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Abstract

Objective:

Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be related to trastuzumab resistance in in vitro studies; however, this issue in clinical studies is controversial. Therefore, we conducted a meta-analysis to assess the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in HER2-positive breast cancer patients.     

辅助化疗联合曲妥珠单抗治疗人表皮生长因子受体-2阳性晚期或转移性乳腺癌的系统评价

目的：系统评价辅助化疗联合曲妥珠单抗治疗人表皮生长因子受体-2（HER2）阳性晚期或转移性乳腺癌的临床效果。方法：检索国内外公开发表的关于辅助化疗联合曲妥珠单抗治疗HER2阳性晚期或转移性乳腺癌的中英文文献,对纳入的研究进行比较。结果：共纳入6篇随机对照试验（RCT）研究。辅助化疗联合曲妥珠单抗治疗HER2阳性晚期或转移性乳腺癌的反应率和病理完全缓解率的风险比（RR）分别为1.46（P=0.02）和0.98（P=0.91）。结论：尽管研究存在一定的局限性,但在不考虑治疗成本的情况下,辅助化疗联合曲妥珠单抗治疗要优于标准治疗,临床上具有较强的可替代性。     

V‐ATPase inhibition overcomes trastuzumab resistance in breast cancer

The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H+‐ATPase (V‐ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V‐ATPase opens a new therapeutic strategy against trastuzumab‐resistant tumor cells in vitro and in vivo. V‐ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro‐survival signaling of the trastuzumab‐resistant cell line JIMT‐1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT‐1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2‐recycling which leads to reduced tumor growth. These results suggest that V‐ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab‐resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2‐signaling in vitro as well as in vivo. V‐ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab‐resistant tumors.     

Effectiveness of Trastuzumab in First‐Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

Background.

The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting.

Materials and Methods.

By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006–2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis.

Results.

Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50–1.26).

Conclusion.

Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials.     

Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%–15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60–65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.