Rodrigo Santa Cruz Guindalini

Monitoring survivin expression in cancer: implications for prognosis and therapy.

Survivin, a member of the inhibitor of apoptosis protein family, is one of the most cancer-specific proteins identified to date. Survivin expression is low or undetectable in most adult tissues, but, alternatively, is overexpressed in a large number of tumors. This multifunctional protein is recognized as a key regulator in apoptosis, proliferation and angiogenesis in the tumor environment. Several studies have shown a correlation between survivin upregulation and poor cancer prognosis, and, as expected, its downregulation or inactivation leads to inhibition of tumor growth. Therefore, survivin has attracted increasing attention both as a potential cancer biomarker and as a new target for anticancer therapies. This review summarizes and discusses survivin expression and its potential as a prognostic and diagnostic biomarker in different types of tumors, as well as provides an overview of the current therapeutic challenges of targeting survivin as a treatment strategy.

Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect.

Genetic anticipation, the earlier onset of disease in successive generations, has been reported in hereditary breast and ovarian cancer syndrome (HBOC), but little is known about its underlying mechanisms. Ascertainment bias has been suggested as a reason in previous studies. Likewise, cohort effect, which may be caused by environmental factors, can be misinterpreted as genetic anticipation.

Resistance to trastuzumab in HER2-positive mucinous invasive ductal breast carcinoma

Resistance to trastuzumab, either primary/de novo resistance or acquired/treatment-induced resistance, is a major clinical concern facing breast oncologists today.1 Here, we describe two cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) with a mucin-producing component that were presumably resistant to trastuzumab.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Validation of questionnaire on the Spiritual Needs Assessment for Patients (SNAP) questionnaire in Brazilian Portuguese

Summary Objectives Spirituality is related to the care and the quality of life of cancer patients. Thus, it is very important to assess their needs. The objective of this study was the translation and cultural adjustment of the Spiritual Needs Assessment for Patients (SNAP) questionnaire to the Brazilian Portuguese language. Methodology The translation and cultural adjustment of the SNAP questionnaire involved six stages: backtranslation, revision of backtranslation, translation to the original language and adjustments, pre-test on ten patients, and test and retest with 30 patients after three weeks. Adult patients, with a solid tumour and literate with a minimum of four years schooling were included. For analysis and consistency we used the calculation of the Cronbach alpha coefficient and the Pearson linear correlation. Results The final questionnaire had some language and content adjustments compared to the original version in English. The correlation analysis of each item with the total score of the questionnaire showed coefficients above 0.99. The calculation of the Cronbach alpha coefficient was 0.9. The calculation of the Pearson linear correlation with the test and retest of the questionnaire was equal to 0.95. Conclusion The SNAP questionnaire translated into Brazilian Portuguese is adequately reliable and consistent. This instrument allows adequate access to spiritual needs and can help patient care.

Genetic Predisposition and Hereditary Syndromes

Hereditary diffuse gastric cancer (GC) is a syndrome with autosomal dominant inheritance related to germline mutations in the CDH1 gene (CDH1-calcium-dependent adhesion protein) leading to changes in the expression of the E-cadherin protein. This syndrome has a high cumulative lifetime risk of developing diffuse gastric and lobular breast carcinomas. Patients who meet the clinical criteria for the syndrome and their relatives should be tested. When a genetic test is positive for a pathogenic variant, the patient should be strongly advised to consider prophylactic gastrectomy. Total gastrectomy for these patients dramatically reduces their risk of GC development. For mutation carriers for whom surgery is not an option, annual standardized endoscopic surveillance is recommended, but it is not as effective as prophylactic gastrectomy. Breast cancer screening is recommended starting at 30 years of age with annual breast magnetic resonance imaging. Prophylactic mastectomy is not routinely recommended, and surgical management should be discussed on a case-by-case basis depending on family history.

Ethics in Clinical Cancer Research

Evidence-based medicine (EBM) has proven to be fundamental in the modern era. The clinical data derived from rigorous research protocols to support EBM has moved towards a high level of complexity to achieve the best level of evidence. However, the pursuit to retrieve organized data intersects with routine medical care. To accommodate significant advances in the area of precision medicine and to streamline the drug development process, newer and even more complex clinical trial design approaches have emerged. In this context, medical innovation not only creates new ethical concerns, but also prompts new considerations in long-standing ethics discussions. In this chapter, we will explore some of the major ethical concerns that arise in the course of modern clinical cancer research, as well as proposing recommendations to protect the rights, safety, and welfare of study subjects.

From colorectal cancer pattern to the characterization of individuals at risk: picture for genetic research in Latin America: From colorectal cancer pattern to the characterization of individuals at risk: picture for genetic research in Latin America

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

Efficacy of anti-HER2 agents in combination with adjuvant or neoadjuvant chemotherapy for early and locally advanced HER2-positive breast cancer patients: a network meta-analysis.

Background Several (neo)adjuvant treatments for patients with HER2-positive breast cancer have been compared in different randomized clinical trials. Since it is not feasible to conduct adequate pairwise comparative trials of all these therapeutic options, network meta-analysis offers an opportunity for more detailed inference for evidence-based therapy. Methods Phase II/III randomized clinical trials comparing two or more different (neo)adjuvant treatments for HER2-positive breast cancer patients were included. Relative treatment effects were pooled in two separate network meta-analyses for overall survival (OS) and disease-free survival (DFS). Results 17 clinical trials met our eligibility criteria. Two different networks of trials were created based on the availability of the outcomes: OS network (15 trials: 37,837 patients); and DFS network (17 trials: 40,992 patients). Two studies—the ExteNET and the NeoSphere trials—were included only in this DFS network because OS data have not yet been reported. The concept of the dual anti-HER2 blockade proved to be the best option in terms of OS and DFS. Chemotherapy (CT) plus trastuzumab (T) and lapatinib (L) and CT + T + Pertuzumab (P) are probably the best treatment options in terms of OS, with 62.47% and 22.06%, respectively. In the DFS network, CT + T + Neratinib (N) was the best treatment option with 50.55%, followed by CT + T + P (26.59%) and CT + T + L (20.62%). Conclusion This network meta-analysis suggests that dual anti-HER2 blockade with trastuzumab plus either lapatinib or pertuzumab are probably the best treatment options in the (neo)adjuvant setting for HER2-positive breast cancer patients in terms of OS gain. Mature OS results are still expected for the Aphinity trial and for the sequential use of trastuzumab followed by neratinib, the treatment that showed the best performance in terms of DFS in our analysis.

Standard cisplatin and etoposide (PE)-based chemotherapy in young adult patients with pineal germinomas.

e12547 Background: Pineal germ cell tumors are very rare, accounting for less than 1% of all intracranial tumors. The peak incidence occurs in the second decade of life. The mainstay of therapy is radiation, especially for germinomas that are very radiosensitive. Leptomeningeal dissemination and histology seem to confer a higher risk for recurrence after radiation. These tumors are also very sensitive to chemotherapy. Attempts to decrease the dose and field of radiation or even to avoid radiotherapy at all have been published. However, the experience with the adult population is very limited. We review retrospectively our experience in adult patients with PGCT that received cisplatin and etoposide-based (PE) chemotherapy in two Brazilian instituition in the last five years. Methods: Consecutive review of patient charts of the last five years of two Brazilian instituitions (Instituto do Cancer de Sao Paulo and Hospital A. C. Camargo). Results: In the last 5 years we identified 6 young adult patients bearin...