What is the best choice of partner chemotherapy with trastuzumab for metastatic breast cancer?

The HER2 gene and its role in pathogenicity in human breast cancer were detected in the 1980s. Trastuzumab is a monoclonal antibody directed against the HER2 membrane receptor. The aim of this article is to describe chemotherapy-trastuzumab combinations that have been evaluated in patients with HER2-positive metastatic breast cancer, and to define the possible standards and options.     

What is the current standard of care for anti-HER2 neoadjuvant therapy in breast cancer?

Neoadjuvant treatment with a sequential anthracycline-taxane-based chemotherapy in combination with trastuzumab (Herceptin) is currently a preferred therapy for patients with HER2-positive breast cancer. This approach is based on the higher pathologic complete response (pCR) of 40% seen with the addition of trastuzumab, compared with a 17% pCR with chemotherapy alone. The pCR can be increased to 75% with dual HER2-receptor blockade and chemotherapy. Higher pCR rates are found in hormone-receptor-negative tumors. Patients with a pCR after chemotherapy and trastuzumab showed a significantly better outcome compared with those who did not have a pCR. The need for additional or alternate treatment options is great in patients who do not achieve a pCR. Addition of lapatinib (Tykerb) or pertuzumab (Omnitarg) to trastuzumab is a therapeutic option. Recent findings suggest pCR might not be the appropriate surrogate for long-term outcome in patients with hormone receptor-positive and HER2-positive tumors.     

Proton-beam vs intensity-modulated radiation therapy. Which is best for treating prostate cancer?

There is a growing interest in the use of proton therapy for the treatment of many cancers. With its unique dose-distribution properties, proton therapy has the potential to improve the therapeutic ratio of prostate radiation by allowing for an increase in dose without a substantial increase in side effects. While much evidence supports this notion in the context of many oncologic sites, only limited clinical data have compared protons to photons in prostate cancer. Therefore, the increasing enthusiasm for the use of protons in prostate cancer has aroused considerable concern. Some have questioned its ability to limit morbidity, and others have questioned its value relative to the cost. In addition, theoretical concerns have been raised about a potential additional risk for secondary malignancies. In this article, we review the current status of the evidence supporting the use of protons in prostate cancer and discuss the active controversies that surround this modality.     

What is the predictor for invasion in non-palpable breast cancer with microcalcifications?

PURPOSE: To assess the presence of invasion in non-palpable breast cancer with microcalcifications. MATERIAL AND METHODS: We investigated 157 patients with non-palpable breast cancer with microcalcifications, who had undergone stereotactic core biopsy or vacuum-assisted breast biopsy and operation at the Cancer Institute Hospital between 1995 and 2001. We investigated the correlation between the area of calcification (maximum range of microcalcifications measured in mm by direct mammography), morphology of calcification on mammography, histological subtype of intraductal carcinoma (comedo or non-comedo) and frequency of invasion, and lymph node metastasis. The chi-square test was used in the statistical analysis and p values less than 0.05 were considered statistically significant. RESULTS: Invasion was observed in 33 of 157 pts (21%), of whom 23 showed minimal invasion, which is less than 0.5 cm in greatest diameter. The risk of invasion was 13% within 10 mm of the microcalcifications (n =70), 25% from 11 to 30 mm (n =59), and 32% more than 31 mm from the microcalcifications (n =28). The risk of invasion was 16% for punctate-round and amorphous type (n =87) microcalcifications, and 27% for pleomorphic and linear-branching types (n =70)(p =0.092). In addition, invasion was found 10% of the time within 10 mm of punctate-round and amorphous type microcalcifications, and 20% of the time at 11 mm or more. On the other hand, invasion was found 15% of the time within 10 mm of pleomorphic and linear-branching type microcalcifications, and 37% of the time at 11 mm or more. In 72 cases of intraductal carcinoma diagnosed by pathological examination, invasion was found in 10 of 31 (32%) comedo type intraductal carcinomas and in 5 of 41 (12%) non-comedo types (p =0.0379). There were 5 cases (3.2%) with axillary lymph node metastasis, all of which widely extended more than 21 mm from the microcalcifications. CONCLUSION: The risk of invasion was 10% within 10 mm of punctate-round and amorphous type microcalcifications, and 37% at more than 11 mm of pleomorphic, linear-branching microcalcifications.     

How to manage the menopause following therapy for breast cancer. is raloxifene a safe alternative?

Raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting. In postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment. Evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels. In randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment. However, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them. In conclusion, raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes. For symptomatic patients, the association of raloxifene with different drugs which have demonstrated efficacy in the control of vasomotor symptoms is now under evaluation.     

What is the optimal therapy for childhood AML?

The use of intensive therapy overa brief period of time has produced dramatic improvements in outcome for pediatric patients with acute myelogenous leukemia (AML), as has been demonstrated in studies by the major cooperative groups in the United States and Europe. Still, despite high-intensity chemotherapy and bone marrow transplantation, only about half of the children diagnosed with AML are cured. Future improvements are unlikely to come from further increases in chemotherapy intensity. Alternative approaches, such as risk-directed therapy based on different prognostic criteria; differentiation therapy with all-trans-retinoic acid (ATRA, Vesanoid), arsenic trioxide (Trisenox), or azacytidine; and immunotherapy with monoclonal antibodies, tumor vaccines, or cytokines may lead to further advances.     

What is the best schedule for administration of gemcitabine-taxane?

Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.     

Obesity in breast cancer – What is the risk factor?

Environmental factors influence breast cancer incidence and progression. High body mass index (BMI) is associated with increased risk of post-menopausal breast cancer and with poorer outcome in those with a history of breast cancer. High BMI is generally interpreted as excess adiposity (overweight or obesity) and the World Cancer Research Fund judged that the associations between BMI and incidence of breast cancer were due to body fatness. Although BMI is the most common measure used to characterise body composition, it cannot distinguish lean mass from fat mass, or characterise body fat distribution, and so individuals with the same BMI can have different body composition. In particular, the relation between BMI and lean or fat mass may differ between people with or without disease. The question therefore arises as to what aspect or aspects of body composition are causally linked to the poorer outcome of breast cancer patients with high BMI. This question is not addressed in the literature. Most studies have used BMI, without discussion of its shortcomings as a marker of body composition, leading to potentially important misinterpretation. In this article we review the different measurements used to characterise body composition in the literature, and how they relate to breast cancer risk and prognosis. Further research is required to better characterise the relation of body composition to breast cancer.     

What is the Japanese consensus on adjuvant chemotherapy in breast cancer?

The international conference of adjuvant therapy for primary breast cancer in St. Gallen and the National Institute of Health Consensus Conference for Breast Cancer Treatment have recommended appropriate treatment for individual subgroups by recurrence risk. However, evidence provided by Japanese clinical trials did not contribute to the consensus recommendations. To compare the risk of recurrence in breast cancer patients between Japan and western countries, a database of Japanese breast cancer patients was analyzed. From 1991 to 2001, approximately 12100 articles listed on MEDLINE were reviewed by abstract, and articles were then selected and reviewed by the authors. According to the AHPC (Agency for Health Care Policy and Research), quality assessment and strength for recommendation of the evidence from clinical trials were classified. Even though there are likely some unknown ethnic differences, we should provide Japanese patients with state of the art treatment for breast cancer in accordance with global standard therapies, which have been evaluated by breast cancer specialists in western countries.     

What is the burden of axillary disease after neoadjuvant therapy in women with locally advanced breast cancer?

Background

The burden of axillary disease in patients with locally advanced breast cancer (labc) after neoadjuvant therapy (nat) has not been extensively described in a large modern cohort. Here, we describe the extent of nodal metastases after nat in patients with labc.

Methods

All patients with labc treated at a single institution during 2002–2007 were identified. Demographic, radiologic, and pathologic variables were extracted. To assess the extent of lymph node metastases after nat, patients were separated into two groups: those with and without clinical or radiologic evidence of lymph node metastases before nat. Axillary lymph nodes retrieved at surgery that had no evidence of metastases after hematoxylin and eosin (h&e) staining underwent further pathology evaluation.

Results

Of the 116 patients identified, 115 were female (median age: 48.5). Before nat, 26 patients were clinically and radiologically node-negative; of those 26, 14 were histologically negative on final pathology. After serial sectioning and immunohistochemistry, 9 of 26 (35%) were node-negative. Of the 90 patients who had clinical or radiologic evidence of lymph node metastases before nat, 23 (26%) had no evidence of lymph node metastases on h&e staining. After serial sectioning and immunohistochemistry, 19 (21%) had no further axillary lymph node metastases. Overall, 76% of patients had pathology evidence of lymph node metastases after nat.

Conclusions

Most patients with labc have axillary metastases after nat. Our findings support axillary lymph node dissection and locoregional radiation in most patients with labc after nat.     

What is the reference cytotoxic regimen for advanced gastric cancer: standard versus optimal therapy?

Advanced gastric cancer is an aggressive disease, with continued poor clinical outcomes. In the past two decades, many clinical trials have been conducted, testing chemotherapy agents in different combinations. However, many of these trials have employed aggressive regimens, which may be not suitable for some patients with advanced disease and poor performance status seen in clinical settings. In addition, geographic and ethnic differences in disease pathogenesis/biology, treatment strategies and drug metabolism make universal application of these trial results difficult. Here, we summarize the extant data on chemotherapy agents in gastric cancer, and try to deduce the best combination(s) that may be utilized in this disease, or that may be suitable for particular subgroup patient populations. Importantly, we discuss future directions - how we need to move away from testing various cytotoxic agent permutations and combinations, towards smarter trials that employ targeted therapies.