Immunotherapy in Breast Cancer: Current Practice and Clinical Challenges.

Immunotherapy is currently approved for a subset of patients diagnosed with advanced triple negative breast cancer (TNBC), based on the phase III randomized controlled trial, IMpassion130. The anti-programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitor atezolizumab combined with nanoparticle albumin-bound (nab)-paclitaxel is currently the standard first-line therapy in patients with metastatic TNBC who have a PD-L1-positive peritumoral immune infiltrate. Although this approval is limited to only a subset of patients, strategies to expand indications in breast cancer for this treatment modality are being extensively evaluated. A substantial need exists for the identification of patient characteristics, disease settings, immune markers, ideal partners for combination with immune checkpoint inhibitors, and the ideal sequence with traditional anticancer therapies. Additionally, in light of the results of the KEYNOTE-522 study of adjuvant pembrolizumab in TNBC, evaluation of immunotherapy in the early disease setting is a subject of great interest. This review article discusses current knowledge on immune checkpoint inhibitors in clinical practice, and provides an overview of a variety of markers evaluated to predict benefit of immunotherapy and of promising new strategies to enhance immune response and enable more patients to benefit from immunotherapy.

Immune manifestations with checkpoint inhibitors in a single Brazilian center: experience and literature review.

OBJECTIVES: The presence of autoimmune events were recorded in patients receiving immune checkpoint inhibitors. MATERIALS & METHODS: Retrospective study in patients receiving immune checkpoint inhibitors (ICIs) during the period of 2012-2019. RESULTS: A total of 554 patients received ICIs of which 123 developed an immune related adverse event. Twenty one (17%) with toxicity were identified as having a pre-existing autoimmune disease and 88 required treatment with corticosteroids or hormone replacement. Thirty two (26%) out of 123 had to temporarily discontinue ICIs due to autoimmune manifestations. Endocrine and skin manifestations were the most prevalent immune disorders in our cohort. In melanoma better efficacy was seen in patients with immune toxicity. CONCLUSION: Autoimmune diseases appear in patients receiving ICIs in this real world experience. Our results differ from other series on the frequency of autoimmunity. Complete discontinuation of ICIs due to autoimmunity was rare.

Management of metastatic cutaneous melanoma: updates in clinical practice.

In recent years, several drugs have been approved for the treatment of patients with metastatic cutaneous melanoma, completely reshaping the landscape of this aggressive disease. Immune therapy with cytotoxic T-lymphocyte antigen 4 and programmed cell death-1 inhibitors yielded significant and durable responses, achieving long-term disease control in up to 40% of the patients. BRAF inhibitors (BRAFi), in combination with MEK inhibitors, also resulted in improved overall survival compared with single-agent BRAFi in patients with BRAFV600-mutated metastatic melanoma. The optimized sequencing and duration of treatment, however, is yet to be found. In this article, we thoroughly review current data and discuss how to best sequence the various treatment modalities available at present, based on four distinct clinical presentations commonly seen in clinic. In addition, we review treatment options beyond checkpoint inhibitors and targeted therapy, which may be required by patients failing such effective treatments.

A Severe, Refractory Case of Mucous Membrane Pemphigoid After Treatment With Pembrolizumab: Brief Communication.

Pembrolizumab is a humanized antibody that targets the programmed death-1 receptor expressed in T cells with high selectivity. This therapeutic is of great importance in cancer immunotherapy yet managing the potential immune-related adverse events remains a concern. Here, we report a rare case of mucous membrane pemphigoid in the oral mucosa, upper respiratory tract, and conjunctiva of a patient with ovarian adenocarcinoma without cutaneous manifestation, which persisted even after pembrolizumab discontinuation. A brief review of pembrolizumab-related bullous pemphigoid cases is presented and possible mechanisms underlying these lesions are discussed.

Identification of risk in cutaneous melanoma patients: Prognostic and predictive markers.

New therapeutic modalities for melanoma promise benefit in selected individuals. Efficacy appears greater in patients with lower tumor burden, suggesting an important role for risk-stratified surveillance. Robust predictive markers might permit optimization of agent to patient, while low-risk prognostic markers might guide more conservative management. This review evaluates protein, gene, and multiplexed marker panels that may contribute to better risk assessment and improved management of patients with cutaneous melanoma.

Melanoma signature in Brazil: epidemiology, incidence, mortality, and trend lessons from a continental mixed population country in the past 15 years.

The current research aimed to understand melanoma epidemiology in Brazil and to evaluate temporal trends in incidence and mortality. The data came from Brazilian Hospital Cancer Registries, Population Based Cancer Registries, and the National Mortality Information System from 2000 to 2014. Descriptive statistics were used for epidemiological and clinical characteristics. To describe trends in change in incidence and mortality rates, the Average Annual Percentage Change (AAPC) was calculated. Between 2000 and 2013, in men, the median incidence rate rose from 2.52 to 4.84, with an AAPC of +21.5% [95% confidence interval (CI): 15.4-28] and in women from 1.93 to 3.22 per 100 000, with an AAPC of +13.9% (95% CI: 8.1-20). Regarding mortality, between 2000 and 2014, the rates went from 0.85 to 0.9 per 100 000 for men (AAPC=+0.8, 95% CI: 0.4-1.1) and from 0.56 for 0.53 per 100 000 for women (AAPC=-0.1, 95% CI: -0.2 to 0). From the database, a total of 28 624 patients with melanoma were included. Most of the patients were females (51.9%), White (75%) and with stage I or II (53.2%). Sex, ethnicity, education level, geographical area of the cancer center, topography, histology, time between diagnosis and treatment, and early death were significantly associated with distant metastases. Brazil is a large country with a very young population and a low rate of melanoma incidence and prevalence that should increase over the years. Understanding the trends attributed to melanoma is important for behavioral counseling interventions that focus on promoting skin cancer prevention.

Immune-mediated Pericarditis With Pericardial Tamponade During Nivolumab Therapy.

A 69-year-old man with metastatic lung adenocarcinoma presented with pericarditis and pericardial tamponade during nivolumab treatment, despite near-complete response on images performed during response evaluation. Further investigation found no evidence of pericardial or pleural cancer involvement, and pathologic evaluation showed immune-related adverse effect. Surgical and steroid treatments were used, with excellent results, and no disease progression on follow-up despite drug discontinuation because of toxicity. Although life-threatening immune-related adverse effects are not frequent when using checkpoint inhibitors, and cardiotoxicity is very rare, different clinical manifestations may occur, and some of them can be fatal in case of inadequate management. It may be challenging to make an etiological diagnosis; however, favorable outcomes can be achieved when prompt directed treatment is promoted.

Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic Solid Tumors.

Abscopal effect is a rare phenomenon characterized by tumor regression of untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied the probability of abscopal effect with radiotherapy associated with anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This study is a retrospective analysis of patients treated with nivolumab or pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer at Antônio Ermírio de Moraes Oncology Center, Brazil. To be eligible for this analysis, patients must have had unequivocal evidence of disease progression on anti-PD1 therapy and subsequent radiotherapy for any tumor site while still receiving anti-PD1. The abscopal effect was characterized as a response outside the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic renal cell carcinoma. The median time to disease progression on anti-PD1 was 3 months. The radiotherapy field included lung, lymph nodes, and bones, with a median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions). Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25% among melanoma patients). Of note, one of them achieved a remarkable complete response lasting >6 months. Three patients with melanoma obtained a significant local response after radiotherapy, despite no response in distant metastases. Eleven patients presented disease progression after radiotherapy. No increased toxicity was observed. In conclusion, no patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.

Taxanes in the management of metastatic castration-resistant prostate cancer: efficacy and management of toxicity.

Androgen deprivation is the therapy of choice in the majority of patients with metastatic prostate cancer. However, a state of castration resistance ultimately occurs after hormone therapy, thus defining metastatic castration-resistant prostate cancer (mCRPC). mCRPC has historically been considered a relatively chemoresistant tumor. However, due to its ability to improve survival and the quality of life in comparison with mitoxantrone, docetaxel has been established as the standard chemotherapeutic agent for first-line therapy since 2004. Moreover, recent results have shown that the novel taxane cabazitaxel is able to prolong the overall survival of patients with mCRPC previously treated with docetaxel. Even though these taxanes display a favorable toxicity profile, their routine use in clinical practice requires knowledge about the most frequent and distinct adverse events that may result from their administration.

Algorithm for the management of metastatic cutaneous melanoma.

Over the last 4 years, various drugs have been approved for the treatment of metastatic cutaneous melanoma. Ipilimumab, an anti-CTLA-4 inhibitor that stimulates antitumor immunity, was the first agent to improve overall survival both in first line and in previously treated patients. Ipilimumab results in long term disease control in approximately 20% of the patients. Vemurafenib was the first BRAF inhibitor (BRAFi) approved and also resulted in improved overall survival compared with dacarbazine in patients with BRAF mutated metastatic melanoma. More recently, another BRAFi, dabrafenib, and a MEK inhibitor, trametinib, were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy. The major feature of such tumor targeted therapy is its high response rate (40-70%) and the rapidity of the responses, resulting in prompt clinical improvement. However, unlike immunotherapy, targeted therapy does not result in long-term treatment free survival. In this paper, we discuss how best to integrate the currently available treatment options including high-dose interleukin-2 (HD IL-2), systemic chemotherapy, ipilimumab and tumor targeted therapy in various clinical scenarios.

Low-dose bevacizumab is effective in radiation-induced necrosis.

BACKGROUND: Radiation-induced necrosis is a complication of brain irradiation. Treatment options are limited. METHODS: The response to treatment with low-dose bevacizumab in 2 patients with radiation-induced necrosis was reported. RESULTS: Both patients with metastatic melanoma, aged 48 and 51 years, had significant symptomatic and radiological improvement with low-dose bevacizumab treatment. Doses as low as 5 mg/kg every 6 weeks and 7.5 mg/kg i.v. every 4 weeks were used and were highly effective. CONCLUSIONS: Low-dose bevacizumab is a solid option in the management of edema associated with radiation necrosis.

Cutaneous melanoma in Latin America: the need for more data / El melanoma cutâneo en América Latina: la necesidad de mßs datos

OBJECTIVE: To identify the scientific literature on cutaneous melanoma in Latin America and compile all available epidemiologic data to demonstrate the need for reliable regional and country-specific data on incidence and mortality estimates. METHODS: Literature searches were conducted in PubMed, Embase, LILACS, and Google Scholar databases for epidemiologic studies from 1 January 2000 to 31 October 2010 related to melanoma in Argentina, Brazil, Colombia, Mexico, Puerto Rico, and Venezuela. A final search on melanoma cases was carried out using country-specific population-based cancer registries. No statistical analyses were conducted. RESULTS: For all six countries, most epidemiological research on cutaneous melanoma consists of hospital-based or case-control studies. Very few studies report incidence and mortality rates. Attempts to estimate disease rates have relied on national incidence and mortality data and information extracted from cancer registries. While predominance of European ancestry is a known risk factor for developing melanoma, the association of melanoma and ethnicity is not well-documented in some of the populations reviewed. Latin Americans are frequently exposed to ultraviolet (UV) radiation due to the tropical weather, high altitude, and thinning ozone layer in some regions. Tanned skin is viewed as healthy and beautiful. While melanoma public health campaigns have been under way in Latin America for decades, increasing melanoma awareness remains imperative. CONCLUSIONS: There is an urgent need to collect accurate epidemiologic melanoma data in Latin America. Future research in the region should include more comprehensive, countryspecific, population-based studies to allow for comparative evaluation of incidence and mortality rates.

OBJETIVO: Identificar la literatura científica sobre el melanoma cutßneo en América Latina y recopilar todos los datos epidemiológicos disponibles, con objeto de demostrar la necesidad de información fiable a escala regional y de país sobre los datos de incidencia y mortalidad. MÉTODOS: Se realizaron búsquedas bibliogrßficas en las bases de datos PubMed, Embase, LILACS y Google Scholar para encontrar estudios epidemiológicos relacionados con el melanoma llevados a cabo del 1 de enero del 2000 al 31 de octubre del 2010 en Argentina, Brasil, Colombia, México, Puerto Rico y Venezuela. Se efectuó una búsqueda final de casos de melanoma mediante la consulta de los registros poblacionales de cßncer de cada país. No se realizó ningún anßlisis estadístico. RESULTADOS: En los seis países, la mayor parte de la investigación epidemiológica sobre el melanoma cutßneo consiste en estudios hospitalarios o estudios de casos y testigos. Muy pocos estudios informan sobre las tasas de incidencia y mortalidad. Los intentos de calcular las tasas de la enfermedad se han basado en los datos nacionales de incidencia y mortalidad, y en la información extraída de los registros de cßncer. Aunque el predominio de la ascendencia europea constituye un conocido factor de riesgo de melanoma, la asociación entre el melanoma y el grupo étnico no puede demostrarse adecuadamente en algunas de las poblaciones estudiadas. Los latinoamericanos estßn frecuentemente expuestos a la radiación ultravioleta como consecuencia del clima tropical, la elevada altitud y la disminución de la capa de ozono en algunas regiones. La piel bronceada se considera como saludable y bella. Aunque hace decenios que se llevan a cabo campa±as de salud pública dedicadas al melanoma en América Latina, es indispensable incrementar la conciencia de esta enfermedad. Conclusiones: Existe la urgente necesidad de recopilar datos epidemiológicos precisos sobre el melanoma en América Latina. Las futuras actividades...

Identifying important breast cancer control strategies in Asia, Latin America and the Middle East/North Africa.

BACKGROUND: Breast cancer is the most frequent cause of cancer death in women worldwide, but global disparities in breast cancer control persist, due to a lack of a comprehensive breast cancer control strategy in many countries. OBJECTIVES: To identify and compare the need for breast cancer control strategies in Asia, Latin America and the Middle East/North Africa and to develop a common framework to guide the development of national breast cancer control strategies. METHODS: Data were derived from open-ended, semi-structured interviews conducted in 2007 with 221 clinicians, policy makers, and patient advocates; stratified across Asia (n = 97), Latin America (n = 46), the Middle East/North Africa (ME/NA) (n = 39) and Australia and Canada (n = 39). Respondents were identified using purposive and snowballing sampling. Interpretation of the data utilized interpretive phenomenological analysis where transcripts and field notes were coded and analyzed and common themes were identified. Analysis of regional variation was conducted based on the frequency of discussion and the writing of the manuscript followed the RATS guidelines. RESULTS: Analysis revealed four major themes that form the foundation for developing national breast cancer control strategies: 1) building capacity; 2) developing evidence; 3) removing barriers; and 4) promoting advocacy - each specified across five sub-ordinate dimensions. The propensity to discuss most dimensions was similar across regions, but managing advocacy was discussed more frequently (p = 0.004) and organized advocacy was discussed less frequently (p < 0.001) in Australia and Canada. CONCLUSIONS: This unique research identified common themes for the development of breast cancer control strategies, grounded in the experience of local practitioners, policy makers and advocacy leaders across diverse regions. Future research should be aimed at gathering a wider array of experiences, including those of patients.

Cutaneous melanoma in Latin America: the need for more data.

OBJECTIVE: To identify the scientific literature on cutaneous melanoma in Latin America and compile all available epidemiologic data to demonstrate the need for reliable regional and country-specific data on incidence and mortality estimates. METHODS: Literature searches were conducted in PubMed, Embase, LILACS, and Google Scholar databases for epidemiologic studies from 1 January 2000 to 31 October 2010 related to melanoma in Argentina, Brazil, Colombia, Mexico, Puerto Rico, and Venezuela. A final search on melanoma cases was carried out using country-specific population-based cancer registries. No statistical analyses were conducted. RESULTS: For all six countries, most epidemiological research on cutaneous melanoma consists of hospital-based or case-control studies. Very few studies report incidence and mortality rates. Attempts to estimate disease rates have relied on national incidence and mortality data and information extracted from cancer registries. While predominance of European ancestry is a known risk factor for developing melanoma, the association of melanoma and ethnicity is not well-documented in some of the populations reviewed. Latin Americans are frequently exposed to ultraviolet (UV) radiation due to the tropical weather, high altitude, and thinning ozone layer in some regions. Tanned skin is viewed as healthy and beautiful. While melanoma public health campaigns have been under way in Latin America for decades, increasing melanoma awareness remains imperative. CONCLUSIONS: There is an urgent need to collect accurate epidemiologic melanoma data in Latin America. Future research in the region should include more comprehensive, country-specific, population-based studies to allow for comparative evaluation of incidence and mortality rates.

Impact of [F-18] FDG-PET/CT in the restaging and management of patients with malignant melanoma.

PURPOSE: To assess the impact of [F-18] FDG-PET/CT on the restaging and changing management of patients with malignant melanoma. METHODS: Seventy-eight patients (32 female, 27-83 years) were reviewed. Treatment planning before and after [F-18] FDG-PET/CT scan was evaluated for changes in the management of the disease. Restaging was classified according to the disease extent as follows: local recurrence, locoregional recurrence or distant recurrence. Initial restaging of patients was as follows: local recurrence in 11 patients, locoregional recurrence in 23 patients and distant recurrence in 44 of 78 patients. All the patients were injected with 370 MBq of [F-18] FDG and imaged from the head to feet after 60 min. All the patients fasted for 4-6 h before imaging and blood glucose levels were below 140 mg/dl. Images were taken using a PET/CT scanner (Siemens Biograph). Two nuclear medicine physicians and a radiologist (all experienced in oncology) interpreted the images. RESULTS: In 27% of the patients the management was changed after the [F-18] FDG-PET/CT studies. Upstaging from locoregional recurrence to distant recurrence occurred in a striking 5 of 23 (22%) patients. The sensitivity, specificity and positive and negative predictive values for lesion detection were 95%, and accuracy was 94.9%. There were two false-positive and two false-negative studies. CONCLUSION: [F-18] FDG-PET/CT seems to be a valuable diagnostic tool in restaging and management of patients with malignant melanoma suspected of recurrence especially in patients with locoregional recurrence and distant recurrence.

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study.

BACKGROUND: The aim of this multicenter phase II study was to demonstrate the activity of the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody cetuximab combined with irinotecan in the treatment of Latin American patients with EGFR-expressing metastatic colorectal cancer (mCRC) in whom previous treatment with an irinotecan-containing regimen had failed. PATIENTS AND METHODS: Patients received cetuximab, as a 400 mg/m2 initial infusion followed by 250 mg/m2 weekly, plus the same irinotecan regimen that had previously failed, until the occurrence of disease progression or unacceptable toxicity. The primary endpoint was response. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. RESULTS: Seventy-nine patients received treatment. One patient had a complete response, 20 had partial responses, and disease was stabilized in 23 patients, giving an overall response rate of 27% and a disease control rate of 56%. The median duration of response was 23.9 weeks. Median PFS was 17.4 weeks, median OS was 9.2 months, and the 12-month OS rate was 38%. The most common adverse events according to System Organ Class were skin and subcutaneous tissue disorders (91% of the patients). Grade 3/4 adverse events occurred in 45 patients (57%), with the most common being diarrhea (20%), neutropenia (11%), and rash (6%). Seven patients (9%) had grade 3/4 acne-like skin rash. No grade 3/4 infusion-related reactions were reported. CONCLUSION: Cetuximab in combination with irinotecan is active and tolerable in Latin American patients with mCRC progressing on irinotecan, with a safety profile similar to that described in European studies.

Final version of 2009 AJCC melanoma staging and classification.

PURPOSE: To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. METHODS: The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. RESULTS: Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. CONCLUSION: Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence.

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-alpha-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled - 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.