14.05.2015

Metastatic liver cancer treatment life expectancy

Cancer stage has a lot of influence on survival rate, which helps the doctor to advise the patient about his condition and what forms of treatment are suitable. When one is diagnosed to have Stage IV cancer, the immediate concern is if the person will be able to survive the disease.
Cancer survival rate refers to the percentage of patients afflicted with a certain form of cancer who survive the disease for a specified amount of time.
Cancer stage has a lot of influence on survival rate, since higher survival rates are usually associated with earlier stages of the disease.
The TNM classification system of cancer describes the tumor size (T) and degree of invasion, the involvement of regional lymph nodes (N) and the presence of spread or metastasis (M) to distant parts of the body.
Cancer staging depends on a combination of the three parameters (tumor size, lymph node involvement and spread of disease).
Cancer staging is a helpful tool for physicians in advising their patients about their options for treatment. The doctor may also help the patient in predicting the outcome of the disease with or without treatment according to research-based statistics. Most types of cancer are classified into four stages, with an additional Stage 0 to distinguish those forms that may later lead to cancer ("pre-cancer" stage). A patient whose cancer cells have invaded other organs aside from its origin is said to be in Stage IV cancer, which usually carries a grim prognosis compared to earlier stages of the disease.
Metastatic melanoma is almost invariably incurable and the prognosis for patients with this disease is quite dismal.
The purpose of this paper is to present a general discussion and summary on the clinical management of metastatic melanoma in Canada.
Systemic chemotherapy was introduced well over 60 years ago as an approach to treating cancer by directly killing tumour cells. The last decade has seen an emergence of therapies targeting the molecular and cellular changes specific to cancer such as specific cell signals and receptors, rather than all rapidly dividing cells.
With these recent advances, the term personalized medicine has been coined and there has been a prominent shift in the general healthcare field as well as in oncology.
In more recent years, emerging molecular data have provided strong genetic support for the notion of biologically distinct melanoma subtypes as mutations in oncogenes, tumour suppressor genes, and others have been discovered.14 Mutated oncogenes include NRAS (neuroblastoma RAS (rat sarcoma) viral (v-ras) oncogene homologue), BRAF, c-KIT (v-kit Hardy- Zuckerman 4 feline sarcoma viral oncogene homologue), GNAQ (guanine nucleotide binding protein (G protein), q polypeptide), and GNA11 (guanine nucleotide-binding protein subunit alpha-11).
These mutations are emerging targets for therapy and because the mutations are generally mutually exclusive, melanoma can be molecularly classified into distinct subtypes which will differ in the response to therapy. Over the last three decades, there have been few developments in more effective treatment strategies for metastatic melanoma.
The heterogeneity of melanoma underscores the need for patient-specific diagnostic and treatment approaches,28 and the recognition of the heterogeneity of the disease is precisely what has driven recent clinical advances. The selection of the most appropriate course of treatment is dependent on a number of factors that include, but are not limited to, the presence of a molecular target, tumour burden, rapidly versus slowly progressing disease, presence of brain metastases, performance status, and the ability to tolerate treatment. The first selective BRAF inhibitor to be developed in the clinical setting is vemurafenib (PLX4032). In a phase I dose escalation study, vemurafenib was administered to 55 patients with solid tumours and to 32 patients with BRAF V600E mutation-positive metastatic melanoma in the extension phase of the study.
The efficacy of vemurafenib in previously treated patients was confirmed in a phase II trial (BRIM-2) of 132 patients with BRAF V600E mutation-positive metastatic melanoma. A total of 618 patients (92%) in the BRIM-3 study underwent at least one assessment for toxic effects. Vemurafenib has also shown promise in the treatment of patients with melanoma metastatic to the brain that harbours a BRAF mutation. It has become evident that metastatic melanoma can become resistant to BRAF inhibition and a number of mechanisms have been proposed. There are several examples of the successful use of monoclonal antibodies as targeted therapies in cancer including HER2 blockade by trastuzumab in breast cancer and CD20 blockade by rituximab in lymphomas.
Cytotoxic T-lymphocyte antigen 4, CD152 (CTLA-4) is a member of the immunoglobulin super-family.
Host immune function has long been observed to play a role in the development and regulation of melanoma growth. Additionally, a phase III trial was conducted that compared DTIC plus ipilimumab versus DTIC plus placebo in previously untreated patients with metastatic melanoma.
As the first assessment of progression occurred at week 12 after the true median, the median values for PFS were similar in the two groups. A distinctive observation of ipilimumab is the variable response patterns, which include a slow, steady decline in baseline lesions, response after an initial increase in the number of lesions, and delayed response in index lesions accompanied by the appearance of new lesions.
Immune-related adverse events (irAEs) are common in patients treated with ipilimumab and may occur in up to 60% of patients.51 The most common irAEs include dermatologic, gastrointestinal (diarrhea), endocrine, and hepatic toxicities.
Over the past few years, there have been major advances in melanoma research and the clinical management of this disease will dramatically shift with the approvals of vemurafenib and ipilimumab. Additionally, dual pathway blockade may be one way to circumvent resistance to vemurafenib. An important component of personalized medicine is the use of predictive biomarkers to aid in selecting patients who have a greater likelihood of responding to a given therapeutic modality.
Adequate infrastructure is necessary to rapidly assess patients’ tumours for expression of these predictive biomarkers and quality-controlled validated assays with a rapid turnaround time need to be performed in appropriately credentialled laboratories with expertise in specific assay systems. Vemurafenib and other BRAF-selective inhibitors should only be prescribed to patients who harbour the BRAF mutation. Despite the clear need for mutation testing in metastatic melanoma, a number of challenges and barriers exist.
Recently, melanoma has earned the designation as “an unlikely poster child for personalized cancer therapy.”29 As new agents transition from the clinical trial context to widespread clinical practice, their use, including the management of AEs, will require optimization. The authors acknowledge medical writing support from Diana Stempak MSc, PhD of New Evidence; this support was funded by Hoffman La-Roche. Arnon Nagler is Professor of Medicine at the Tel Aviv University, Tel Aviv, Israel, and the Director of both the Division of Hematology and the Bone Marrow Transplantation and Cord Blood Bank at the Chaim Sheba Medical Center, Tel Hashomer, Israel. This concern, also medically known as the prognosis, depends on many factors, including availability of treatment and one's general health condition. Statistics often refer to a five-year period where scientific surveys on these patients are based, although these data do not specify whether the patients are still undergoing treatment or are completely cancer-free after five years. To describe one's cancer stage physicians use the TNM Staging System which uses criteria that are similar for different types of cancer except malignancies in the brain and blood.
Different degrees of tumor size or invasion, involvement of lymph nodes and spread to other organs are further specified in numbers to describe in more detail the stage of malignancy. A Stage I cancer therefore is a localized stage of malignancy, where a tumor is relatively small, has not invaded surrounding tissues or spread to other organs.
A patient with Stage I may need less aggressive treatment than a patient with Stage II cancer, but a patient with Stage IV cancer may choose to have supportive therapy rather than radical procedures. This includes prediction of one's 5-year survival rate, which may also help the patient choose a treatment option which suits his preferences. Alsoknown as carcinoma in situ (CIS), this is an early form of cancer where there is a flat lesion with no invasion of malignant cells into the surrounding tissue.
Tumors in this stage are usually smaller than 2 centimeters (cm) and are localized to the part of the body where it originated. Tumors in this stage measure 2-5 cm but are still localized since they have not invaded other tissues or spread to distant sites. Tumors in this stage may be of any size, affecting nearby lymph nodes and showing evidence of spread (metastasis) to other organs or regions of the body.
The five-year survival rate for patients in this stage may depend on different factors such as the type of cancer he has, his overall general health, the type of treatment used and the patient's will power to overcome the disease. Liver cancer survival rates and treatments will vary depending on the stage of cancer and other factors. Historically, the median survival time for a patient with metastatic melanoma is six to nine months and the five-year overall survival (OS) rate is less than 5%. These agents function by varying mechanisms such as damaging deoxyribonucleic acid (DNA), impairing DNA repair, inhibiting microtubule formation and acting as alkylating agents.
Used as monotherapy or in combination with other agents, these targeted therapies have significantly improved patient outcomes and the safety of treatment over previously accepted standards.11 Almost every malignancy can be divided into molecular subsets that vary in prognosis, natural history, and response to treatment. The goal is to understand the relevant characteristics underlying a particular individual’s disease, which include both disease and host factors, and tailor therapy to that individual or disease. Cytotoxic and immunological therapies that have been available to date did not target specific pathways in cells, and most were not effective in controlling the disease regardless of the primary origin of the disease. Tumour suppressor genes that are mutated include PTEN (phosphatase and tensin homologue), P53, and others.
Systemic approaches that have been evaluated to date for metastatic disease include cytotoxic chemotherapy as single agents and in multi-drug combinations including dacarbazine (DTIC), temozolomide and platinum agents (carboplatin, paclitaxel, and protein-bound paclitaxel) and immunotherapies including the cytokines interferon-? (IFN) and interleukin-2 (IL-2).5 Treatment with DTIC, alone or in combination, has resulted in low response rates, rare durable responses, and no impact on survival. The two leading agents that are changing the landscape of melanoma therapy are the highly selective BRAF inhibitor, vemurafenib, and the anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab. The current standard of care for metastatic melanoma in Canada is clinical trials and this will continue to be the case as combination therapies are investigated to further improve outcomes. It plays a central role in regulating the MAPK (mitogen-activated protein kinase) signalling pathway that normally regulates cell growth, division, and differentiation.31,32 (Figure 1) The MAPK signalling pathway has long been associated with human cancers due to frequent oncogenic mutations identified in RAF (rapidly growing fibrosarcoma) family members. All 32 patients in the extension phase received the recommended phase II dose of 960 mg twice daily. The confirmed overall response rate (ORR) assessed by an independent review committee (IRC) was 53% (95% confidence interval [CI]: 44–62), with 6% achieving a complete response (CR) and 47% achieving a partial response (PR).


Vemurafenib was associated with statistically significantly improved OS and PFS compared with DTIC. Preliminary results suggest that vemurafenib is well tolerated and that it has activity in metastatic melanoma that has metastasized to the brain.47 A phase II study is currently ongoing to confirm these results. It is expressed on a subset of activated human T lymphocytes and regulatory T-cells, and plays a critical role in the control of activated T-cells.
Although the first two types of responses would be captured using the standard Response Evaluation Criteria In Solid Tumours (RECIST), the last two atypical responses would likely be classified as progressive disease by RECIST.
These drugs differ from one another by mechanism, treatment course, clinical outcomes, and AEs, as summarized in Table 8. Evidence currently suggests that the MAPK pathway is activated in order to bypass the BRAF blockade. This interaction between the receptor and ligand and the resulting signalling drives melanoma differentiation, proliferation, survival, and migration.57 The c-KIT pathway activates downstream pathways including MAPK, PI3K, and Src. Although limited in number thus far, clinical experiences confirm KIT as a melanoma therapeutic target and patients have experienced dramatic and durable responses to treatment with agents such as imatinib, nilotinib, and dasatinib.
For metastatic melanoma specifically, this would lead to improved outcomes in this traditionally difficult-to-treat population while reducing the likelihood of exposing patients to potentially ineffective therapy and unnecessary side effects. This requires coordination between members of the multidisciplinary team, namely surgeons, pathologists, dermatologists, and medical oncologists. The cobas® test is a real-time polymerase chain reaction assay designed to detect the BRAF V600E mutation. Recently, several studies have described the challenges of treating non-BRAF V600E melanoma cell lines with a BRAF inhibitor.
Some of these are unique to metastatic melanoma and others are more general and apply to other therapeutic areas. Furthermore, new strategies will be needed to treat patients in whom resistance to BRAF inhibitors develops. With the recent approval of these new agents, a shift in the treatment paradigm and in attitude is needed.
Petrella is an advisor and consultant for Bristol-Meyers Squibb, Glaxo SmithKline, Hoffmann-La Roche, and Merck.
Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. Kimberly Blackwell is a medical oncologist, Professor of Medicine, and Assistant Professor of Radiation Oncology at Duke University Medical Center in Durham, North Carolina, U.S. Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. Rummel is the head of the Department for Hematology at the Clinic for Hematology and Medical Oncology at the Justus-Liebig University-Hospital, Giessen, Germany.
Eichhorst graduated from the University of Munich School of Medicine in 1997, having completed a doctoral thesis in the field of hematology that focused on evaluating the signal transduction pathways of Hodgkin cells. Michael Hallek is Professor of Medicine, and Director and Chair of the Department of Internal Medicine I at the University of Cologne in Cologne, Germany, where he oversees internal medicine, hematology, hemostaseology, oncology, intensive care, infectious diseases, and immunology. Knowing what stage one's cancer is mostly determines his probability of surviving based on research. An over-all five-year survival rate of 80% would mean that for every 100 patients with the disease, 80 would probably live for at least another five years, and 20 would probably not survive this period of time.
For instance, a tumor described as T1 is much smaller and confined than a tumor that is described as T4. On the other hand, cancer which is in Stage IV may have a tumor of any size, may have affected the lymph nodes and has definitely spread to other distant organs such as the brain, liver or bones. This late, locally advanced stage affects lymph nodes nearby and it may be difficult to differentiate from stage II cancer. As mentioned above, the five-year survival rate is expressed as the percentage of patients who will probably live up to 5 years after diagnosis of the disease based on research on patients with the same type and stage of cancer. Until recently, there were few treatment options available for metastatic melanoma and those available demonstrated low efficacy and significant toxicity. Without question, metastatic melanoma is a devastating disease with a need for novel treatment strategies that has been unmet until the discovery and development of novel agents such as BRAF (v-raf murine sarcoma viral oncogene homologue B1) inhibitors (vemurafenib and dabrafenib) and novel immunotherapies (ipilimumab).
The goal is to raise awareness in the oncology community about new treatment approaches to metastatic melanoma, and to highlight the importance of rapid coordination and testing for biomarkers that are the targets for a more personalized approach to cancer therapy. However, the cytotoxic effects are not limited to tumour cells alone, they also target any rapidly dividing cell in the body including bone marrow cells, hair follicles, and gut mucosal cells resulting in the classic side effects of myelosuppression, mucositis, alopecia, nausea, and vomiting. In other words, it is the use of the right drug, at the right dose, for the right patient, at the right time.13 While significant advances have been made in a number of tumour types, little change has been realized in the treatment of metastatic melanoma until very recently. In spite of the identification of a wide variety of genetic abnormalities and potential molecular targets in melanoma, effective targeted agents are required in order to advance patient outcomes. Some of these molecular alterations appear to be linked to the degree of sun exposure, histology, and physical location of the primary melanoma.18,19 The incidence of some of these mutations is summarized in Table 2. Additional targets and new agents against these targets are currently being studied in phase III trials. In the extension phase, vemurafenib was found to have high single-agent clinical activity with unprecedented response rates of 81% in patients, including those who had previously received multiple lines of chemotherapy, as well as at metastatic sites such as bone and liver that are typically refractory.
Additionally, four of the 10 patients who had a BRAF V600K mutation had a PR to vemurafenib.
In the vemurafenib group, 10 patients were later found to have BRAF V600K mutations; of these patients, four had a PR (40%). Grade 2 or 3 photosensitivity skin reactions were observed in 12% of the patients and it was noted that grade 3 photosensitivity reactions characterized by blistering could have been prevented with the application of sunblock.
As a negative regulator of the immune system, it plays an important role in endogenous and vaccine-induced antitumour immunity.
At week 24, patients with stable disease or an objective response who did not have a dose-limiting AE were eligible for maintenance therapy consisting of placebo or ipilimumab every 12 weeks until progression, toxicity, or the end of the study.52 The OS results from this ongoing study are similar to the previous phase III trial and are summarized in Table 7 and Figure 5.
Targeting this pathway further downstream in the cascade can be achieved using MEK inhibitors such as GSK1120212 (trametinib).
A phase II study of imatinib reported high response rates and prolonged PFS in c-KIT-positive patients,58 and a single agent trial has demonstrated responses59 and a phase II trial with nilotinib is ongoing.
In general terms, there are several criteria that should be met to successfully implement biomarker testing. These include funding of the molecular test, turnaround time, logistical issues surrounding sample collection and handling, and timing of the test amongst others.
Rational combination with other agents including other targeted therapies and immune therapies is one approach to overcome drug resistance. There now exists a renewed sense of hope in a therapeutic area that was previously burdened by poor outcomes. Stewart is currently a pro - fessor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Ma - lignancies at the University of Calgary. She is the Director of the Breast Cancer Program at the Duke Cancer Institute and serves on the national Scientific Advisory Board of the Susan G.
She became a consultant in internal medicine after finishing an internship at Klinikum Grosshadern in the Department of Internal Medicine III at the University of Munich.
Nagler received his medical training at the Hebrew University-Hadassah Medical School, Jerusalem, Israel, specializing in hematology at the Rambam Medical Center, Haifa, Israel.
Cancer staging therefore helps the doctor to advise the patient about his condition and what forms of treatment are suitable, and to predict his survival rate in the next few years.
The overall physical and mental health of the patient may be affected and survival rate is very low. A 60% 5-year survival rate therefore indicates that it is estimated that 60 out of every 100 patients will live for 5 years after diagnosis while the rest (40 of 100) will probably die. The discovery, development and recent approval of novel agents such as vemurafenib (a selective BRAF inhibitor) and ipilimumab (a novel immunotherapeutic agent) has resulted in patients experiencing prolonged survival with manageable adverse events. With recent notable improvements in outcomes in patients with metastatic melanoma, the prognosis of this disease may not be as dismal as it was in the past. Today, metastatic melanoma is at the forefront of the movement toward personalized medicine. While the prognostic importance of many of these markers has not yet been demonstrated, the prognostic significance of BRAF has recently been shown.
Until recently, oncologists specializing in melanoma watched significant advances being made in other malignancies. In 2002, it was discovered that approximately 50% of human melanomas harbour an activating mutation in BRAF, raising the possibility that melanoma could be amenable to targeted therapy.34 While a number of agents with some BRAF inhibitory activity have been studied in oncology, recent efforts have been focusing on the highly selective BRAF inhibitors.
A clear impact on progression-free survival (PFS) was also observed but these findings were only seen in patients with the V600E mutation.
Benefit was observed in all subgroups studied including patients with poor prognosis including those with M1c disease or elevated lactate dehydrogenase (LDH).
As expected, the most common severe toxic effects in the DTIC group were fatigue, nausea, vomiting, and neutropenia.
Resting lymphocytes do normally express CTLA-4 but expression is transiently up-regulated upon binding of the T-cell receptor.
Patients who were treated with ipilimumab experienced an improvement in OS, PFS, and ORR.51 The key efficacy results for this trial are summarized in Table 6. There are also different models for biomarker screening that ought to be considered including a central reference centre model that uses a single imposed platform versus a network of reference centres and different platforms.


It is very likely that within the next several years, melanoma patients will be routinely screened for the presence of a panel of specific markers to determine the most appropriate therapeutic approaches that will undoubtedly have a positive impact on outcomes. Mok became an Assistant Professor in the Department of Clinical Oncology at the Chinese University of Hong Kong in 1996.
Goethe University Hospital in Frankfurt, Germany, obtaining his licence to practice medicine in 1995. He carried out a postdoctoral research fellowship in hematology and bone marrow transplantation at Stanford University Hospital in Palo Alto, California, U.S. Hallek was head of the Gene Therapy Program at the Gene Center of the University of Munich and of the Clinical Cooperation Group for Gene Therapy at the National Centre for Research on Environment and Health (GSF) in Munich.
This is just an estimate and not an exact number, since many factors influence the progress of one's disease. In the case of vemurafenib, the importance of selecting patients in this new era of personalized medicine has been underscored. While this paper is evidence-based, it does not reflect a systematic literature review and is not meant to be used as a consensus guideline. To better understand how these new treatments fit into the treatment paradigm, it is important to look at how melanoma can be classified. AEs resulted in dose modification or interruption in 129 of 336 patients (38%) in the vemurafenib group and in 44 of 282 patients (16%) in the DTIC group. Up-regulation of CTLA-4 on the surface of cytotoxic T-cells results in inhibition of proliferation of these cells. Long-term durability data are pending and are anxiously awaited.55 Results of phase III trials are anticipated. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation.
She received her undergraduate degree in bioethics at Duke University, and her medical degree at Mayo Clinic Medical School. Following this, he completed his doctoral degree and residency, obtained board certification in internal medicine, and was awarded his PhD from J.W. Eichhorst became a leading member of the German CLL Study Group and has served as the group’s secretary since 2005. While challenges exist to implementing rapid, efficient biomarker testing, this is an essential component of therapy that will improve outcomes in this traditionally difficult-to-treat population.
In the vemurafenib group, 61 patients (18%) developed cutaneous AEs with a cutaneous squamous-cell carcinoma or kertoacanthoma, or both. Further research is warranted to identify and validate the optimal treatment regimen regarding ipilimumab dosing and scheduling as well as combinations. It is likely that testing will require some centralization as not all treatment centres have a molecular or skin pathologist. Claveau is a consultant and investigator for Bristol-Meyers Squibb, Glaxo SmithKline, Hoffmann-La Roche, Merck, and Novartis. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. He holds an honorary professorship at the Guangdong Provincial People’s Hospital in Guangdong, China, and a guest professorship at the Peking University School of Oncology.
She has published several papers on the treatment of chronic lymphocytic leukemia (CLL) and has acted as principal investigator for several phase II and III clinical trials that evaluated treatment optimization in CLL.
Nagler has been working in the fields of bone marrow transplantation for hematological malignancies, including non-Hodgkin lymphoma, and hemato-oncology, for the last 20 years.
Hallek was appointed Director of the Center of Integrated Oncology (CIO), the joint comprehensive cancer centre of the Universities of Cologne and Bonn.
The recent approval of these new agents necessitates a shift in the treatment paradigm and in attitude. Strategies will need to be implemented to allow for efficient testing in order to avoid treatment delays. Blackwell completed an internal medicine internship and residency, and a hematology-oncology fellowship at Duke University Medical School. He is heavily involved in several professional societies and committees, including being President-elect of the International Association for the Study of Lung Cancer.
Professor Rummel’s current research focuses on novel treatment approaches in hematological malignancies, most notably follicular and other indolent lymphomas as well as hairy cell leukemia and also immune thrombocytopenic purpura (ITP). As a result, a renewed sense of hope now exists in a therapeutic area that was previously burdened by poor outcomes. Furthermore, multiplexing of tests for various biomarkers will be important particularly in melanoma because there is a limited amount of tissue available. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. In addition to maintaining an active clinical practice, she has served as a principal investigator on many clinical trials in breast cancer. He is the chair of the Study group indolent Lymphomas (StiL) and principal investigator of several ongoing clinical trials in leukemias, lymphomas, and ITP.
Eichhorst is currently an Associate Professor at the University of Cologne and a consultant in hematology and internal oncology at the University Hospital of Cologne. Nagler established the first public cord blood bank and performed the first cord blood transplantations from related and unrelated donors in genetic and malignant hematological disease. This tissue may be limited to the original melanoma, which can be very small and it may be difficult to obtain more. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Her research interests include breast cancer angiogenesis, breast cancer in younger women, endocrine therapy, and HER2-targeted therapy. Mok is the Associate Editor of several journals and has published over 130 articles in peer-reviewed journals.
He is actively involved in a number of professional scientific societies, he is a reviewer for a number of journals, and has several published book chapters and papers to his credit. His main clinical interests include stem cells, bone marrow transplantation, hematological malignancies, cord blood biology, and adoptive cell-mediated immunotherapy. Multiplexing allows for the screening of an array of mutations at once (BRAF, cKIT, NRAS, and GNAQ amongst others).
Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. Blackwell has authored or co-authored over 40 articles or book chapters appearing in journals such as Clinical Cancer Research, the Journal of Clinical Oncology, Cancer, Radiation Research, and Molecular Cancer Therapeutics.
Nagler has written numerous articles, reviews, and chapters for peer-reviewed journals, and is the principal investigator for a number of clinical studies.
Given that the incidence of BRAF mutations is approximately 50%, fast and accurate testing is especially critical in order to initiate vemurafenib in a timely fashion, particularly in rapidly progressing disease. He is the principal inves - tigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, and Lancet Oncology. In the past year, she has reviewed for several grant committees and peer-reviewed journals. Biochemotherapy for the treatment of metastatic malignant melanoma: a clinical practice guideline.
Cerebral melanoma metastases: a critical review on diagnostic methods and therapeutic options. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.
RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032.
The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Vemurafenib Improves Overall Survival Compared to Dacarbazine In Advanced BRAFV600E-mutated Melanoma: Updated Survival Results From a Phase III Randomised, Open-label, Multicentre Trial. An open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases. Patient Responses to Ipilimumab, a Novel Immunopotentiator for Metastatic Melanoma: How Different are these From Conventional Treatment Responses?
Molecular testing for BRAF V600 mutations in the BRIM-2 trial of the BRAF inhibitor vemurafenib in metastatic melanoma.




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