Cagatay Arslan

Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature.

Importance of the field: Hormone and human epidermal growth factor receptor 2 (HER-2) receptors are two important pharmaceutical targets that affect the survival of patients with metastatic breast cancer. Discordance of hormone and HER-2 receptors were reported in a series of studies. Receptor status was reported to change in both directions, yet alteration occurs mostly in the loss of positivity for both receptors. We do not know both the exact mechanism of this process or the contribution rate of technical mistakes; a number of mechanisms might be responsible. Factors suggested include: tumor heterogeneity, clonal selection of tumor cell subpopulations, genetic instability of tumor cells, local or systemic treatments, the time interval between primary tumor and metastasis, receptor status determination techniques, and the site of metastasis. Areas covered in this review: Studies of estrogen, progesterone and HER-2 receptor discordance between primary and metastasis of breast cancer are summarized. Laboratory evaluation of estrogen, progesterone and HER-2 receptors, and possible causes of receptor discordance, are summarized. Literature data are reviewed; the major shortcoming of these studies is that they are mostly retrospective. What the reader will gain: The reader will read a concise literature review about the studies on estrogen, progesterone and HER-2 receptor discordances between primary and metastasis of breast cancer. Take home message: We do not know whether the changes in receptor expression account for a true biological phenomenon or may result from inconsistent measurement. However, in light of current data, for the treatment plans that target the receptors, biopsy specimen from the metastatis of breast cancer must also be evaulated for alterations in the receptor status.

Pharmacotherapy of triple-negative breast cancer

The term ‘triple-negative breast cancer’ defines tumors that do not express estrogen receptors, progesterone receptors or Her2 on immunohistochemical analysis. This subgroup accounts for 15% of all types of breast cancer. Histologically, triple-negative breast cancers are poorly differentiated and are characterized by an aggressive clinical history. A significant overlap exists in biological and clinical characteristics of basal-like breast cancer and triple-negative breast cancer. Treatment options are limited, as these tumors lack a therapeutic target and are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. As there are no specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, local and systemic relapse rates are high due to the adverse biology of the disease. Triple-negative breast cancer has many histological and genetic similarities with BRCA-1-associated breast cancer, suggesting a common pathogenesis and the potential use of common chemotherapeutics in both cancers. This review discusses current and future treatment options in the light of the new insights in major proliferative pathways active in the pathogenesis of triple-negative breast cancer.

Advances in PARP inhibitors for the treatment of breast cancer

Introduction: Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors. Areas covered: Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer. Expert opinion: PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.

Screening Colonoscopy Participation in Turkish Colorectal Cancer Patients and their First Degree Relatives

BACKGROUND This study aimed to research the awareness of screening colonoscopy (SC) among patients with colorectal cancer (CRC) and their relatives. METHODOLOGY A questionnaire form including information and behavior about colonoscopic screening for CRCs of patients and their first-degree relatives (FDRs) was prepared. RESULTS A total of 406 CRC patients were enrolled into the study, with 1534 FDRs (siblings n: 1381 and parents n: 153) . Positive family history for CRC was found in 12% of the study population. Previous SC was performed in 11% of patients with CRC. Mean age of the patients whose FDRs underwent SC was lower than the patients whose FDRs did not (52 vs 57 years; p<0,001). The frequency of SC in FDRs was 64% in patients diagnosed CRC under 35 years of age. Persons having a positive family history of CRC had SC more often (51 vs 22%, p<0,001). FDRs of patients having a higher educational level and income had SC more frequently. CONCLUSIONS When screening for CRC is planned, elderly subjects, those with family history for CRC, and those with low educational and lower income should be given especial attention in order that they be convinced to undergo screening for CRC.

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update

Introduction: Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. Areas covered: Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. Expert opinion: Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.

Emerging drugs in metastatic breast cancer: an update

Introduction: The incidence of breast cancer at an advanced stage has decreased in the modern world due to screening programs and usage of novel chemotherapy agents at an adjuvant setting. Recurrence is the major problem seen in > 50% of breast cancer patients diagnosed at an early stage. Developing new drugs for metastatic breast cancer is a huge and challenging research area. Areas covered: Emerging drugs showed positive results in clinical studies and agents in routine clinical usage are updated. Current treatment strategies as a combination of biologic agents and overcoming drug resistance are discussed. Literature search is made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts. Expert opinion: A number of drugs caused survival benefit for advanced breast cancer. Hundreds of new studies with tens of agents are conducted for treatment of metastatic breast cancer. Tumor resistance and treatment related toxicities are unavoidable which are two main search areas for improving metastatic breast cancer management. Understanding the pathways of genesis and progression yielded many targets for treatment. However, cure in metastatic breast cancer is still a far aim and new agents and treatment strategies are needed.

Secondary haematological malignancies in the BCIRG 001 study

Updated results of the BCIRG 001 study showed that improvements in eff icacy noted at 5 years with the addition of docetaxel to anthracycline-based treatment were maintained at 10 years for both progression-free survivial and overall survival in women with nodepositive breast cancer. Congestive heart failure—one of two important late-term toxic eff ects of anthracyclines in the adjuvant treatment of breast cancer—was reported for 26 (3%) of 744 patients given docetaxel, doxorubicin, and cyclophosphamide (TAC), and for 17 (2%) of 736 given fl uorouracil, doxorubicin, and cyclophosphamide (FAC; p=0·175). The second toxic eff ect, secondary haematological malignancies, will be a growing problem in the near future with regards to increased survival. These malignancies arise in 0·3–1·7% of patients with breast cancer who are receiving antineoplastic chemotherapy. In the 10 year analysis, the BCIRG 001 study investigators reported secondary hematological malignancies in six patients in the TAC group and three patients in the FAC group (p=0·51). The absence of a significant diff erence between the two groups might be related to the low frequency of these events. The heightened risk in patients given TAC might be attributable to the increased use of granulocyte colonystimulating factor (G-CSF) in this group; however, no directly reported data are available. Use of G-CSF was mandatory after the first episode of febrile neutropenia in the study, and febrile neutropenia was more frequent in TAC patients than in those given FAC (25% vs 3%; p<0·0001). Acute myeloid leukaemia (AML) and myelodisplastic syndrome (MDS) are among the most reported secondary haematological malignancies in patients with breast cancer. Alkylating drugs, topoisomerase inhibitors, growth factors, and radiation treatment are the most studied causal factors. AML associated with alkykating drugs generally takes place after 5–7 years of drug exposure and after 2–3 years from topoisomerase-II inhibitor treatment. Some findings have shown that colony-stimulating factors increase the risk of AML and MDS; however, no consensus exists about how they increase the risk. The raised risk of secondary haematological malignancy possibly related to increased G-CSF treatment in patients given TAC should be considered when treatment decisions are made. Access to cancer medicine in Iran

Alpha-Fetoprotein Response After Locoregional Therapy for Hepatocellular Carcinoma

TO THE EDITOR: We read with great interest the report by Riaz et al, in which they demonstrated that the response of serum alphafetoprotein (AFP) level after locoregional therapy in patients with hepatocellular carcinoma (HCC) was a useful surrogate marker to determinate tumor response and survival. In this study, AFP response was seen in 81 (64.8%) of 125 patients treated with chemoembolization and radioembolization. Also, the authors reported that AFP response was a prognostic factor for overall survival in univariate and multivariate analyses. It is still unclear whether serial AFP measurement or AFP/tumor volume for monitoring treatment response in patients with HCC should be used. Some studies have shown that serum AFP level might be used as a surrogate marker for response to systemic chemotherapy. A significant correlation between serum AFP levels and both size and number of HCC lesions has been reported. AFP/tumor volume may be a better prognostic indicator for patients with HCC than serum AFP value alone. Also, significant correlation between higher AFP levels and higher stages has been reported. Because the results of a multivariate analysis give important messages to readers, the analysis should be carefully used. For accurately interpreted results of a study, the sample size should be sufficient to perform multivariate analysis. Some authors have recommended that a minimum of 20 patients per predictor should be used for an accurately interpreted multivariate analysis. Also, each parameter considered to be a prognostic factor must be evaluated before univariate or multivariate analysis is performed, because one factor may interact with the others. We think that the statistical assessment is the most important limitation of the study by Riaz et al. The study included a total of 125 patients and six prognostic factors, such as stage, performance status, Child Pugh class, WHO response, European Association for the Study of the Liver response, and AFP response, which were evaluated for multivariate analysis. We think that the sample size of the study was quite small for multivariate analysis, and the interaction probability among prognostic factors analyzed in the study was quite high. We believe that this problematic issue may have affected the results presented in the report.

Gene Arrays, Prognosis, and Therapeutic Interventions

Among women, breast cancer accounts for one-third of cancer cases and is the second most frequent cause of death. Improvements in treatment agents and screening procedures have increased the diagnosis of early breast cancer and survival rates. Adjuvant chemotherapy and endocrine treatment decrease the mortality of early breast cancer by approximately 50 %. However, not all early breast cancer patients benefit equally from adjuvant endocrine treatment and/or chemotherapy. Patients at high risk are classically identified based on clinicopathological factors, such as age, tumor size, histopathological grade, nodal status, hormone and HER2 receptor positivity, and menopausal status. However, for patients with early breast cancer, using these standard clinicopathological factors might not thoroughly show the individual risk of disease recurrence and the benefits from adjuvant systemic chemotherapy. Many patients with early breast cancer do not derive benefit from adjuvant systemic chemotherapy. Quality-of-life issues, acute and long-term side effects of systemic chemotherapy, and the cost of unnecessary treatments are the main factors of concern for this group of patients. Quantitative approaches for defining prognoses and for individualizing treatments are required. In recent years, molecular signatures of gene expression have been correlated with breast cancer recurrence risk. Several tests for genomic expression have been developed and validated on specimens from previous phase III studies to improve the prognostication of early breast cancer patients and/or the prediction of adjuvant systemic treatment. The most commonly used genomic expression-based tests used for prognostic information and for the prediction of chemotherapy benefits in early breast cancer are summarized below.

Do we need new trials for the abiraterone, enzalutamide and cabazitaxel in metastatic castrate-resistant prostate cancer for confirmation of treatment indications?

information about men with low volume MPC, who were admitted only to the later part of the study. High-volume disease was defined as visceral organ metastasis and/ or ≥4 bone metastasis of at least one outside of axial skeleton [6]. The GETUG-15 study was another study in similar patient population with negative results [7]. However, the STAMPEDE trial confirmed the benefit of docetaxel to improve OS in men with hormone-sensitive MPC, most of whom presented with metastatic disease at diagnosis [8]. Treating men with MPC with docetaxel in the endocrine-sensitive phase of the disease might change the course of tumor biology and influence the probability of response to subsequent therapies. Previous studies of abiraterone and enzalutamide before or after docetaxel treatment, and cabazitaxel in docetaxel pre-treated patients in mCRPC were all made in patients who did not receive docetaxel for endocrine-sensitive disease. We do not have data for use of abiraterone, enzalutamide and cabazitaxel in men with mCRPC who received docetaxel in the endocrinesensitive phase of their disease yet, and we do not know whether these drugs will have the same efficacy in this new population of mCRPC patients. We need new trial results for the confirmation of treatment indications of those drugs in this newly emerging mCRPC patient population. However, there are a number of ongoing trials with abiraterone, enzalutamide and other new generation antiandrogens in early metastatic prostate cancer and combinations of them at mCRPC and treatment indications for those agents might change in recent years.