Molecular Testing and Personalized Medicine

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“Perez EA, Suman VJ, Davidson NE, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 2006; 24: 3032–38.) ) Lack of accurate testing can lead to misdiagnosis or ineffective or ina…”

Human cancer subtypes are traditionally classified according to certain clinical and pathological parameters that include the anatomical site of origin, microscopic histomorphology, tumor size, tumor grade, and regional lymph node involvement. This is a well-established classification scheme that relies on molecular and genetic information that helps classify different cancer subtypes and predict their behavior. In clinical practice, tests for tumor-specific characteristics can provide prognostic information and immediate treatment options.

Using the right therapy, for the right patient, at the right time has implications for the cost-effectiveness of therapies and affects treatment costs. Genetic and molecular analysis of tumors has advanced the field of oncology and ushered in a new era in personalized cancer care. In this section, we look at the current state of cancer diagnosis in Latin America and how new technologies and targeted treatments are being introduced into the clinic.

Centralized laboratory tests and quality control

Laboratory systems that perform cancer diagnosis tests vary from country to country and are not well characterized in the cancer literature. A few studies have compared expert evaluation or centralized laboratory tests with regional evaluations or evaluations carried out by inexperienced personnel (Table 8).

In these studies, cancer diagnostic tests, including vaginal Pap smear, cervical, gastric, and prostate biopsy evaluations, as well as immunohistochemical evaluation for breast cancer, all had low concordance rates. Reasons for differences in assessment from local and reference laboratories could be due to low volume of tests for specific cancers at regional health centers and hospitals, lack of experience with specific cancer diagnostic criteria, or problems technicians related to testing in local laboratories. For example, in a study conducted in Uruguay, (1)Delgado L, Fresco R, Santander G, et al. Tumor expression of HER2, estrogen and progesterone receptors and their relationship with clinicopathological characteristics in Uruguayan patients with breast cancer Rev Med Urug 2010; 26: 145–53 researchers reported lower HER2 positivity rates than expected in women with early breast cancer. Although the reasons for this finding are not fully understood, aspects of the immunohistochemistry tests in the study, such as technical errors in interpreting the results, variation in the antibodies used by the test manufacturers, and the protein breakdown, could have led to more false negative results. (2)Delgado L, Fresco R, Santander G, et al. Tumor expression of HER2, estrogen and progesterone receptors and their relationship with clinicopathological characteristics in Uruguayan patients with breast cancer. Rev Med Urug 2010; 26: 145– 53.

Testing of HER2 is technically difficult and has been problematic since its inception. (3)Perez EA, Suman VJ, Davidson NE, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 2006; 24: 3032–38.) ) Lack of accurate testing can lead to misdiagnosis or ineffective or inadequate treatment, which can affect survival. A study conducted in Colombia showed that the poor evaluation of the Pap smear explained why screening efforts in the country had not affected mortality from cervical (cervical) cancer. (4)Cendales R, Wiesner C, Murillo RH, Pineros M, Tovar S, Mejia JC.Quality of vaginal smear for cervical cancer screening: aconcordance study. Biomedica 2010; 30: 107–15. Several Latin American countries (Argentina, Brazil , Cuba, Mexico, Guatemala, El Salvador, Honduras, Nicaragua, Colombia, Venezuela, Ecuador, Paraguay, Peru and Uruguay) participate in the International System of External Quality Assessment (IEQUAS, for its initials in English), which helps improve and standardize laboratory diagnostics and provide measurements of laboratory proficiency. (5)WHO, PAHO. Health in the Americas, 2012 edn. Regional outlook and country profiles. Washington, DC: Pan American Health Organization, 2012. ((International Federation of Clinical Chemistry and Laboratory Medicine. Latin-American Confederation of Clinical Biochemistry (COLABIOCLI). Http://www.ifcc.org/executive-board-and-council/regional-federations/colabiocli-latin-american-conf-clinicalbiochemistry/ (accessed Jan 22, 2013).

Effect of delay in diagnosis

Diagnostic tests for cancer must be done on time. Various studies carried out in Brazil, Mexico and Peru indicate that there are delays in pathological anatomy evaluations that can affect diagnosis and the start of treatment. (6)Gage JC, Ferreccio C, Gonzales M, Arroyo R, Huivin M, Robles SC. Follow-up care of women with an abnormal cytology in a low-resource setting. Cancer Detect Prev 2003; 27: 466–71. (7)Rezende MC, Koch HA, Figueiredo Jde A, Thuler LC. Factors leading to delay in obtaining definitive diagnosis of suspicious lesions for breast cancer in a dedicated health unit in Rio de Janeiro. Rev Bras Ginecol Obstet 2009; 31: 75–81 . (8)Bright K, Barghash M, Donach M, de la Barrera MG, Schneider RJ, Formenti SC. The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico. Breast 2011; 20 (suppl 2): ​​54–59. In studies conducted in Brazil and Mexico, the average delay between the visit to the doctor and the diagnosis of breast cancer was 6–7 months. (9)Unger-Saldana K, Pelaez-Ballestas I, Infante-Castaneda C. Development and validation of a questionnaire to assess delay in treatment for breast cancer. BMC Cancer 2012; 12: 626 (10)Rezende MC, Koch HA, Figueiredo Jde A, Thuler LC. Factors leading to delay in obtaining definitive diagnosis of suspicious lesions for breast cancer in a dedicated health unit in Rio de Janeiro. Rev Bras Ginecol Obstet 2009; 31: 75–81. (11)Bright K, Barghash M, Donach M, de la Barrera MG, Schneider RJ, Formenti SC. The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico. Breast 2011; 20 (suppl 2): 54–59. The mean time from biopsy to histological diagnosis ranged from 0 to 68 days in a study conducted in Brazil, and delays of up to 299 days were recorded for immunohistochemistry results. (12)Trufelli DC, Miranda Vda C, Santos MB, et al. Analysis of delays indiagnosis and treatment of breast cancer patients at a public hospital. Rev Assoc Med Bras 2008; 54: 72–76 (in Portuguese). In a study carried out in Peru, (13)Gage JC, Ferreccio C, Gonzales M, Arroyo R, Huivin M, Robles SC. Follow-up care of women with an abnormal cytology in a low-resource setting. Cancer Detect Prev 2003; 27: 466 –71. Women who had abnormal Pap smear after cervical biopsy and who had a cervical biopsy often had to wait 4–5 months before receiving the definitive diagnosis. When cancer diagnosis is delayed, the stage of the disease is affected and an adverse outcome becomes more likely. Delays of more than 12 weeks in diagnosis are considered of suboptimal quality for breast cancer, and survival of cervical cancer is affected by delays of more than 5 weeks. (14)EC, Dahrouge S, Samant R, Mirzaei A, Price J. Radical radiotherapy for cervix cancer: the effect of waiting time on outcome. Int J Radiat Oncol Biol Phys 2005; 61: 1071–77. (15)Richards MA , Smith P, Ramirez AJ, Fentiman IS, Rubens RD. The influence on survival of delay in the presentation and treatment of symptomatic breast cancer. Br J Cancer 1999; 79: 858–64. These delays, which cause an unfavorable change The tumor stage before the start of therapy is considered one of the reasons why there are higher mortality rates in Latin American countries than in countries with superior resources.

Improving cancer diagnosis in Latin America

To improve cancer diagnosis, factors affecting laboratory quality should be considered, including the availability of laboratory supplies, essential equipment, competent personnel, resources for adequate training, and quality control evaluations of systems. current. (16)Petti CA, Polage CR, Quinn TC, Ronald AR, Sande MA. Laboratory medicine in Africa: a barrier to effective health care. Clin Infect Dis 2006; 42: 377–82. At the national level, governments and Public health systems must support centralized laboratory networks and establish standard tests. (17)Peter TF, Shimada Y, Freeman RR, Ncube BN, Khine AA, Murtagh MM. The need for standardization in laboratory networks. Am J Clin Pathol 2009; 131: 867–74. Centralized laboratory networks can improve the access to high-level cancer diagnoses and provide regulatory oversight to coordinate operational functions and quality control. Diagnostic tests that are not performed frequently, including genetic tests or molecular analysis of the tumor, should be carried out exclusively in centralized laboratories. The efforts made by the Ministry of Health and the National Cancer Institute in Brazil demonstrate this approach. By 2014, the Brazilian Ministry of Health aims to establish ten laboratories across the country to perform molecular tests for lung cancer. (18)Ferreira CG. Epidemiological-Molecular Profile of small cell lung cancer not Brazil. In Edital Result FAPERJ No. 27/2010 FAPERJ / SESDEC / MS / CNPq Research Program for or SUS: Gestão Compartilhada em Saúde — 2010. http://www.faperj.br/boletim_interna.phtml?obj_id=7645. (accessed Feb 19, 2013). Similar initiatives are needed for lung cancer and other cancers elsewhere.

At the regional level, initiatives to improve the quality of tissue samples, technical manipulation of tissue specimens, slide preparation and special staining processes should be supported. Tumor samples should be stored under acceptable conditions (preferably in the form of formalin-fixed and paraffin-embedded tissues) and should be archived for future diagnostic tests that may be necessary in the aftercare of a patient. At the same time, it is necessary to establish biobanks at the national or regional level. Initiatives such as the National Tumor Bank of Brazil, which has 38,000 stored samples, or the Network of Tumor Banks of Latin America and the Caribbean (REBT-LAC) should be encouraged. (19)Network of National Cancer Institutes. Biobanks: Peruvian expert visits INCA in Brazil for the standardization of procedures. Http://www2.rinc-unasur.org/wps/wcm/connect/RINC/site/home/noticias/biobancos_experto_del_peru_visita_el_inca_de_brasil_para_fines_estandarizacion_de_procedimentos (accessed Feb 17, 2013 Tumor files are also very valuable as a repository for research studies, with the appropriate consent. Like what has been recommended for HIV / AIDS in Africa, another approach to improving quality would be to establish a laboratory accreditation system for cancer in Latin America.256 There are two programs in Brazil that have demonstrated the potential of education to improve the accuracy of cancer diagnosis. In Belo Horizonte, agreement among pathologists in the interpretation of premalignant breast lesions increased after standardized diagnostic criteria were examined and representative images were shown.242 More recently, an effort was made in Pernambuco to establish the accuracy of childhood cancer diagnosis after the introduction of a specific training program and the establishment of telepathology in the region. (20)Santiago TC, Jenkins JJ, Pedrosa F, et al. Improving the histopathologic diagnosis of pediatric malignancies in a lowresource setting by combining focused training and telepathology strategies. Pediatr Blood Cancer 2012; 59: 221–25.

Genetic predisposition: BRCA mutations

Knowledge of cancer genetics in the Latin American population is limited, and most studies in the region have focused on the frequency of BRCA mutations. The BRCA gene mutation, in contrast to many other genetically inheritable mutations for cancer, directly affects clinical treatment options. Women in whom a BRCA mutation has been found can be educated on modifiable lifestyle factors to reduce their risk of cancer, and may be offered more intensive surveillance, prophylactic surgery, or chemoprevention. From available studies, BRCA mutation rates in Latin America appear to be similar to rates in the US or Europe, but may be higher in some countries (Table 9). The prevalence of BRCA mutations in unselected women in the Bahamas corresponds to the highest rate detected in any country in the region. (21)Donenberg T, Lunn J, Curling D, et al. A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas. Breast Cancer Res Treat 2011; 125: 591–96 The high prevalence of the BRCA mutation in America Latin could be explained by the historical Jewish migration from modern Spain and Portugal to Latin America during the Age of Discovery during the XV to XVII centuries. (22)Velez C, Palamara PF, Guevara-Aguirre J, et al. The impact of Converso Jews on the genomes of modern Latin Americans. Hum Genet 2012; 131: 251–63.

In Latin America, genetic testing for BRCA or other cancer predisposing mutations is not widely available, and is prohibitively expensive when offered. In low-income settings, genetic testing is often too expensive to be offered to a large number of people, but some form of alternative testing must be considered. Tests to detect high-frequency mutations instead of sequencing entire genes, or analyzing a specific population that could benefit from the result, could offset the high cost. Testing for BRCA mutations in a region such as the Bahamas, where the prevalence is high, could allow for early intervention and save lives, and could save costs in the long term.

Expansion of cancer genetic research in Latin America

There is increasing interest in the application of crossbreeding mapping to identify genes that influence complex traits, such as cancer, in populations that are related by ancestry to genetically differentiated populations. This approach has been effective and more economical than full-genome high-density association studies, and has led to the identification of fixed genetic variants in native populations. (23)Seldin MF. Admixture mapping as a tool in gene discovery. Curr Opin Genet Dev 2007; 17: 177–81. (24)McKeigue PM. Prospects for admixture mapping of complex traits. Am J Hum Genet 2005; 76: 1 –7 This approach has potential value for cancer research, and the Latin American population is an ideal cohort for this type of study. Latin American populations are made up of a mix of Native Americans, Europeans, and Africans; However, the great variation in the number of indigenous lines that exist in the different populations of Latin America implies that the effectiveness of mapping by miscegenation varies substantially depending on the geographic region considered. (25)Price AL, Patterson N, Yu F, et al. A genomewide admixture map for Latino populations. Am J Hum Genet 2007; 80: 1024–36. (26)Wang S, Ray N, Rojas W, et al. Geographic patterns of genome admixture in Latin American Mestizos. PLoS Genet 2008; 4: e1000037 An analysis of the year 2008 (27)Wang S, Ray N, Rojas W, et al. Geographic patterns of genome admixture in Latin American Mestizos. PLoS Genet 2008; 4: e1000037 reported that the genetic load of Native American ancestors was 70% in northwestern Argentina and 20% in Brazil, Costa Rica, and Colombia. This study also showed that the burden of African ancestors was low (less than 5%) in most of the populations examined, except in the Colombian Caribbean region and eastern Brazil. This genetic heterogeneity of the populations of the continent could modify the pattern of many diseases, especially cancer, and the response to pharmacological treatments. (28)Wang S, Ray N, Rojas W, et al. Geographic patterns of genome admixture in Latin American Mestizos. PLoS Genet 2008; 4: e1000037

Genetic and molecular tests for cancer

Little effort (study) has been made to assess genetic differences from malignancies in Latin America, and our knowledge of cancer in the mestizo population is based primarily on information obtained from the Hispanic population in the United States. (29)Haile RW, John EM, Levine AJ, et al. A review of cancer in US Hispanic populations. Cancer Prev Res (Phila) 2012; 5: 150–63. However, a few targeted studies have begun to be conducted to the genetic characterization of tumors in Latin America. The most comprehensive study to date has characterized the mutation frequency of the epidermal growth factor gene (EGFR) and KRAS for non-small cell lung carcinoma (NSCLC), including 1,150 samples from Argentina, Colombia, Peru, and Mexico. (30)Arrieta O, Cardona AF, Federico Bramuglia G, et al. Genotyping non-small cell lung cancer (NSCLC) in Latin America.J Thorac Oncol 2011; 6: 1955–59. Overall, the mutation frequency was 33.2% for EGFR and 16.6% for KRAS. The distribution was homogeneous for Argentina (19.3%), Colombia (24.8%) and Mexico (31.2%), and very high in Peru (67%), possibly explained by the influence of population migration from Asia to the region or due to different rates of exposure to wood smoke. (31)Arrieta O, Cardona AF, Federico Bramuglia G, et al. Genotyping non-small cell lung cancer (NSCLC) in Latin America. J Thorac Oncol 2011; 6: 1955–59. (32)Arrieta Rodriguez OG, Tellez E , Martinez-Barrera L, et al. Woodsmoke exposure as a survival predictor in non-small cell lung cancer with response to erlotinib: an open label phase II study. Proc Am Soc Clin Oncol 2007; 25 (suppl 18): abstr 18029. No explanation has been found for the existence of a higher percentage of EGFR-positive lung adenocarcinomas in Latin America compared to developed countries, but factors such as the different genetic susceptibility of the population, the rates of infection, have been implicated. HPV infection, nutritional status, and exposure to wood smoke. (33)Arrieta Rodriguez OG, Tellez E, Martinez-Barrera L, et al. Woodsmoke exposure as a survival predictor in non-small cell lung cancer with response to erlotinib: an open label phase II study. Proc Am Soc Clin Oncol 2007; 25 (suppl 18): abstr 18029. (34)Bria E, Milella M, Cuppone F, et al. Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta- analysis Ann Oncol 2011; 22: 2277–85 Subgroup analyzes of Latin American patients with EGFR mutations show a response to a specific treatment; These efforts are informative and show that EGFR mutations are not limited to population cohorts in which they were initially described — that is, non-smoking women in Asia. (35)Sholl LM, Yeap BY, Iafrate AJ, et al. Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers. Cancer Res 2009; 69: 8341–48 Changing this type of cancer perceptions is important to improve care. Knowing that EGFR mutations are common in lung cancer in Peru will draw attention to this group of patients who may not have access to EGFR inhibitor treatments. These findings should also promote further studies on the question of whether EGFR-mutated lung cancer is associated with exposure to wood smoke. (36)Wilking N, Jönsson B. A pan-European comparison regarding patient access to cancer drugs. http://ki.se/content/1/c4/33/52/Cancer_Report.pdf accessed Oct 14, 2012). (37)Arrieta O, Cardona AF, Federico Bramuglia G, et al. Genotyping non-small cell lung cancer (NSCLC) in Latin America. J Thorac Oncol 2011; 6: 1955–59. (38)Arrieta Rodriguez OG, Tellez E, Martinez-Barrera L, et al. Woodsmoke exposure as a survival predictor in non-small cell lungcancer with response to erlotinib: an open label phase II study. Proc Am Soc Clin Oncol 2007; 25 (suppl 18): abstr 18029 If this association is established, it could guide public health strategies in countries like Peru.

Personalized oncology in Latin America

Characterizing the prevalence of cancer predisposition genes, mutations, and molecular markers in different tumors in Latin America is a first step in providing a personalized approach. Regional efforts have begun to achieve such characterizations (Tables 9 and 10), and these efforts will ultimately reduce cancer morbidity and mortality, and cost in Latin America. To support these initiatives, pathologists who perform, interpret, and regulate complex molecular and genetic data will need highly specialized training and education in genetic medicine. The varied genetic ancestry of the Latin American population poses opportunities and challenges. Studies carried out by the Brazilian Pharmacogenetic Network to investigate the genetic heterogeneity of the population are underway. (39)Suarez-Kurtz G. Pharmacogenetics in the Brazilian population. Front Pharmacol 2010; 1: 118. Oncologists, physicians, and all care providers involved in cancer detection, diagnosis, and treatment need up-to-date training on how to integrate genetic and molecular information into clinical practice. For example, BRCA testing in high-risk patients should be done only after a comprehensive genetic consultation, as is standard practice in countries where testing is established.

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