Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2–positive breast cancer

© 2018, Hong Kong Academy of Medicine Press. All rights reserved. Introduction: The management of human epidermal growth factor receptor 2 (HER2)–positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond. Methods: This retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as first-line treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication. Results: Among 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progression-free survival was 6.0 (95% confidence interval, 3.3-9.8) months and the median overall survival had not been reached by the data cut-off date. Grade 3 or 4 toxicities included thrombocytopaenia (13.5%), raised alanine transaminase (8.1%), anaemia (5.4%), and hypokalaemia (2.7%). No patient died as a result of toxicities. Conclusions: In patients with HER2-positive advanced breast cancer who have been heavily pretreated with anti-HER2 agents and cytotoxic chemotherapy, T-DM1 is well tolerated and provided a meaningful progression-free survival of 6 months and an overall survival that has not been reached. Further studies to identify appropriate patient subgroups are warranted.Link_to_subscribed_fulltex

Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma

Elevated levels of circulating cell-free Epstein-Barr virus (EBV) DNA have been detected in plasma and serum samples from nasopharyngeal cancer (NPC) patients by quantitative real time PCR (qPCR) test. This qPCR test for circulating EBV DNA was found to be useful in the clinical management of NPC patients. For instance, EBV DNA qPCR test has good sensitivity and specificity in the detection of NPC at disease onset. Increase of the viral DNA load was found in NPC patients at late stages of disease. High EBV DNA load at disease onset or detectable viral load post-treatment was associated with poor survival or frequent relapse in NPC patients. Residual EBV DNA load after primary treatment could be a useful indicator to justify adjuvant chemotherapy. The qPCR test might also be applied to define a poor prognostic group in patients at early stage (I/II) for implementing concurrent chemo-radiotherapy (chemo-RT) to improve patients' outcome. The test is also useful to monitor distant metastases or response to radiotherapy, chemo-RT or surgery. Supplementary tests, however, are needed to pick up EBV negative WHO type I NPC and test improvement is needed to increase sensitivity in detecting stage I disease and local recurrence. © 2013 Elsevier Ltd. All rights reserved.Link_to_subscribed_fulltex

Central nervous system metastasis from nasopharyngeal carcinoma: A report of two patients and a review of the literature

BACKGROUND. Central nervous system (CNS) metastasis from nasopharyngeal carcinoma (NPC) is an extremely rare occurrence, although direct intracranial invasion is not infrequent in patients with NPC at a locally advanced stage. Only five other patients have been reported in detail in the English literature. METHODS. The clinical records of two such patients with NPC who were diagnosed with metastasis to the spinal cord (intradural) and to the occipital lobe, respectively, were reviewed. The literature was searched for a review of similar incidents. RESULTS. Both patients had locally advanced disease at the time of presentation and were treated with neoadjuvant chemotherapy and radical radiotherapy. The CNS metastases in both patients were accompanied by disease recurrences in multiple sites after a prolonged period of clinical remission. Spread through cerebral spinal fluid was postulated for the patient with spinal cord metastasis, and hematogenous spread was postulated for the patient with brain metastasis. Aggressive surgical resection with or without postoperative radiotherapy conferred reasonable survival and symptom control. The patient with brain metastasis died 6 months later of lung metastasis, whereas the other patient is still alive 40 months from the diagnosis of spinal metastasis. CONCLUSl0NS. Good symptom control and disease control can be achieved for patients with CNS metastasis after surgery with or without radiotherapy. After aggressive therapy, the ultimate survival depends on control of extracranial disease. © 2002 American Cancer Society.Link_to_subscribed_fulltex

Experience with the management of ovarian germ cell tumors in Chinese patients

Treatment results of 37 consecutive patients with primary ovarian germ cell tumors (OGCTs) were analyzed. Thirty-three were referred after initial laparotomy and four were first seen at relapse. Four patients with stage I dysgerminoma and grade 1 immature teratoma were observed after operation without recurrence. There was also no relapse in eight patients with dysgerminoma given postoperative irradiation (whole abdomen, median 30 Gy). Twenty-five patients (3 dysgerminomas, 11 immature teratomas, 9 endodermal sinus tumors, and 2 mixed germ cell tumors) received short-term cis-platinum- based chemotherapy. Six out of eight measurable tumors treated by chemotherapy had complete remission. Complete follow-up information was obtained in 35 out of 37 patients. The 4-year actuarial survival rates of the whole group and those referred immediately after initial surgery were 94.1 and 100%, respectively. cis-Platinum was substituted by carboplatin in eight cases but this did not affect treatment result. Nonetheless, deaths occurred in two of four patients referred at relapse with extensive disease and initially treated with suboptimal regimens. Chemotherapy-induced side effects were common but mostly tolerable and were related to cis-platinum and bleomycin. The results of this series show that cis-platinum-based chemotherapy is so effective that nearly 100% cure can be achieved in OGCTs and suggest that it is important to institute optimal chemotherapy from the start. On the other hand, common side effects of treatment and possible late toxicities make it desirable for future studies to see whether chemotherapy intensity could be reduced in patients with good prognosis. © 1994 by Academic Press, Inc.Link_to_subscribed_fulltex

Management of nasopharyngeal carcinoma

© Springer International Publishing Switzerland 2011, 2016. Nasopharyngeal carcinoma is a distinctly radiosensitive and chemosensitive tumor. Best quality radiotherapy is demanded to build up the complex concave high-dose zone for this critical location. Intensity-modulated radiotherapy (IMRT) is advocated; image guidance to ensure setup precision and adaptive re-planning if major deviations from intended dose distribution occur during the treatment course are useful improvements if resources allow. Stringent dose constraint to organs at risk should be attempted to minimize late toxicities. Addition of cisplatin-based concurrent-adjuvant chemotherapy is recommended for patients with stages III-IVB and high-risk stage IIB diseases. Contemporary series using IMRT together with extensive use of chemotherapy reported very encouraging long-term results with locoregional control in excess of 85 % at 5 years; the key remaining problems are advanced T4 disease and distant failure. Further improvement of efficacy by more potent systemic therapy and changing chemotherapy sequence to induction-concurrent is being explored. The plasma level of Epstein-Barr Viral Deoxyribonucleic Acid is a well-established tool for non-keratinizing carcinoma for prognostication and monitoring disease progress. Integrated fluorodeoxyglucose positron emission tomography and computed tomography is useful for excluding distant metastases and posttreatment persistent/recurrent disease. Early detection of failure is critical; and aggressive treatment should be attempted as long survival could be achieved for patients with limited failure. Different salvage methods and reported results are summarized.Link_to_subscribed_fulltex

Exploring protein regulations with regulatory networks for cancer classification

This paper proposes a novel modeling technique for understanding cancer signal pathway and applies to cancer classification. In the approach, specific to a cancer group, a regulatory network is constructed between biomarkers and is optimized towards minimizing its energy function that is defined as disagreement between input and output of the network. The non-linear version of this network is achieved by imposing a sigmoid kernel function. The proposed approach is tested on protein profiling data of nasopharyngeal carcinoma and is compared with support vector machines with linear and radial basis function kernels. © 2008 IEEE.Link_to_subscribed_fulltex

Characterizing the malignancy and drug resistance of cancer cells from their membrane resealing response

In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ∼ 2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement.Link_to_subscribed_fulltex

A possible prognostic role of immunoglobulin‐G antibody against recombinant Epstein‐Barr virus BZLF‐1 transactivator protein ZEBRA in patients with nasopharyngeal carcinoma

Background. Epstein‐Barr virus BZLF‐1 replication activator (ZEBRA) is involved in the switch from viral latency to a productive cycle. Previous immunofluorescent study has shown that patients with nasopharyngeal carcinoma (NPC) have elevated immunoglobulin‐G (IgG) antibody titres against recombinant ZEBRA protein (ZEBRA/IgG). Methods. The prognostic role of ZEBRA/IgG was further investigated by enzyme‐linked immunosorbent assay (ELISA) in 110 NPC patients under long period of clinical follow‐up. Results. Ninety‐seven percent (85 of 88) of the patients with NPC had significantly higher ZEBRA/IgG titres (geometrical mean titre, i. e., GMT = 8397) than normal Chinese individuals (GMT = 233 and P < 0.0001). Based on Kaplan‐Meier analysis, the actuarial survival in patients with high ZEBRA/IgG titres (25%) after radiotherapy was significantly lower than that of those with low (76%; P = 0.0008) or intermediate titres (62%; P = 0.0036), although the titres taken before treatment did not bear such a relationship. Subdividing the patients into either individual UICC or Ho's stages, those with late‐stage disease (UICC Stage 4 and Ho's Stages 3 and 4) and with high ZEBRA/IgG titres also had poorer prognosis than those with disease of the same stages but who had low titres. Poor prognosis in those with high titres could be associated with a high risk of distant metastasis because consistent titre increase was found in the majority of patients who later developed distant metastasis either in the lung or liver. Only a minimal increase was found in patients with recurrence in the cervical lymph nodes. No consistent increase was observed, however, in patients whose disease was in remission or the majority of those with bone metastasis or local recurrence in the nasopharynx. Conclusion. The postradiotherapy ZEBRA/IgG titre could be a potentially useful marker for differentiating NPC patients with poor prognosis from those at high risk for the development of distant metastasis to the lung or liver. Copyright © 1994 American Cancer SocietyLink_to_subscribed_fulltex

Identification of serum amyloid A protein as a potentially useful biomarker for nasopharyngeal carcinoma (multiple letters)

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Circulating Epstein-Barr virus DNA in serum of patients with lymphoepithelioma-like carcinoma of the lung: A potential surrogate marker for monitoring disease

Purpose: The purpose of this work was to study the sera of patients with lymphoepithelioma-like carcinoma (LELC) of the lung for circulating EBV DNA. Experimental Design: Prospectively collected serum samples from five female patients with advanced, inoperable LELC of the lung were measured for free circulating EBV DNA using a quantitative PCR technique. EBV-encoded small RNA (EBER)-1 was assayed in serial serum samples of three of the rive patients, either from the start or during the initial phase of chemotherapy/radiotherapy until their terminal event or last follow-up. There was only a single-point sample for analysis in the fourth and fifth patients. Six other patients with LELC of the lung were also retrospectively identified, and their sera were tested for EBER-1 at either the first visit plus the last follow-up visit (n = 2), the first visit only (n = 2), or the last follow-up visit only (n = 2). Results: Prospectively collected serum samples from five patients and retrospectively collected serum samples from two patients who had clinical disease at initial serum measurement showed detectable levels of EBER-1. Retrospectively collected serum samples from four patients with no clinical disease had negative sera. There is consistent correlation between the clinical response to treatment and subsequent clinical course of LELC and serum EBER-1 levels in the three prospective patients with longitudinal serum monitoring. Conclusions: This study shows for the first time that free EBV DNA can be detected in the serum of patients with LELC of the lung and further suggests the feasibility of its use for monitoring response to therapy in advanced cases.Link_to_subscribed_fulltex