Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

HLA-G 14 bp Ins/Del (rs66554220) Variant Is Not Associated with Breast Cancer in Women from Western Mexico.

HLA-G is a physiology and pathologic immunomodulator detrimentally related to cancer. Its gene is heavily transcriptionally and post-transcriptionally regulated by variants located in regulator regions like 3'UTR, being the most studied Ins/Del of 14-bp (rs66554220), which is known to influence the effects of endogen cell factors; nevertheless, the reports are discrepant and controversial. Herein, the relationship of the 14-bp Ins/Del variant (rs66554220) with breast cancer (BC) and its clinical characteristics were analyzed in 182 women with non-familial BC and 221 disease-free women as a reference group. Both groups from western Mexico and sex-age-matched (sm-RG). The rs66554220 variant was amplified by SSP-PCR and the fragments were visualized in polyacrylamide gel electrophoresis. The variant rs66554220 was not associated with BC in our population. However, we suggest the Ins allele as a possible risk factor for developing BC at clinical stage IV (OR = 3.05, 95% CI = 1.16-7.96, p = 0.01); nevertheless, given the small stratified sample size (n = 11, statistical power = 41%), this is inconclusive. In conclusion, the 14-bp Ins/Del (rs66554220) variant of HLA-G is not associated with BC in the Mexican population, but might be related to advanced breast tumors. Further studies are required.

Adaptación y evaluación de la eficacia de un programa psicoeducativo de navegación para disminuir síntomas de ansiedad y depresión en mu-jeres mexicanas con cáncer de mama / Design and evaluation of the efficacy of a psychoeducational navigation program to reduce symptoms of anxiety and depression in Mexican women with breast cancer

Objetivo:El cáncer de mama (CAM) es un problema de salud pública mundial. La ansiedad y depresión son las principales comorbilidades que aquejan a este sector, el programa psicoeducativo de navegación (PPN) se presenta como una estrategia psicosocial eficaz en hospitales públicos de México. Método: Se realizó la adaptación del PPN y la evaluación de eficacia en 47 mujeres con CAM de tres hospitales de la Zona Metropolitana de Guadalajara. El PPN integró acompañamiento emocional, educación para la salud y técnicas de relajación. Se evaluaron los síntomas y los niveles de ansiedad y depresión, pre-post intervención con la Escala Hospitalaria de Ansiedad y Depresión (HADS). Resultados: Se encontró una disminución en los síntomas de ansiedad pre-test (M= 6,79, DT= 4,01) y pos-test (M= 4,19, DT= 3,03), igual que en los síntomas de depresión antes (M= 6,02, DT= 4,07) y después (M= 4,23, DT= 3,05). Se obtuvieron diferencias estadísticamente significativas entre las evaluaciones pre y post intervención tanto en las dimensiones, como en la puntuación global (p<0,001). Conclusiones: El PPN mostró eficacia para disminuir los síntomas y los niveles de ansiedad y depresión en mujeres mexicanas con CAM. Sugerimos replicar el programa en otros contextos de atención oncológica en seguimiento a las normativas nacionales (AU)

Objective: Breast cancer (BC) is a public health problem. Anxiety and depression are the main comorbidities that afflict this sector, the navigation psychoeducational program (NPP) is presented as an effective psychosocial strategy in public hospitals in Mexico.Method: The NPP was adapted and its efficacy evaluated in 47 women with BC from three hospitals in the Guadalajara Metropolitan Area. The NPP integrated emotional accompaniment, health education and relaxation techniques. Symptoms and levels of anxiety and depression were evaluated pre-post intervention with the Hospital Anxiety and Depression Scale (HADS). Results: A decrease was found in anxiety symptoms pre-test (M= 6.79, SD= 4.01) and post-test (M= 4.19, SD= 3.03), the same as in depression symptoms before (M= 6.02, SD= 4.07) and after (M= 4.23, SD= 3.05). Statistically significant differences were obtained between the pre- and post-intervention evaluations both in the dimensions and in the global score (p<0.001).Conclusions: The NPP showed efficacy in reducing symptoms and levels of anxiety and depression in Mexican women with BC. We suggest replicating the program in other cancer care contexts in compliance with national regulations (AU)

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

The -174G>C and -596G>A Polymorphisms Are Not Associated with Circulating IL-6 Levels in Breast Cancer Patients from Jalisco, México.

Introduction: Interleukin-6 (IL-6) is a circulating proinflammatory cytokine that fulfills an important role in the survival and proliferation of cancer cells. Overexpression of IL-6, possibly due to the -174G>C and -596G>A polymorphisms in the IL6 gene, has been shown to be related to breast cancer (BC) and a more aggressive course of the disease. Aim: To determine the influence of the -174G>C and -596G>A polymorphisms of the IL6 gene on the circulating levels of IL-6 in BC patients from Jalisco, México. Methodology: Genotyping of the two polymorphisms was carried out on 208 BC patients and 219 healthy controls through polymerase chain reaction-restriction fragment length polymorphism analyses. In addition, the plasma IL-6 concentration levels were measured in the BC patients. Results: There was no significant association between BC and the IL-6 alleles and genotypes (-174G>C, p = 0.276; -596G>A, p = 0.762) under study. Similarly, there were no significant differences in the mean plasma IL-6 concentrations associated with the polymorphisms that were analyzed (-174G>C, p = 0.839; -596G>A, p = 0.848). Conclusions: No evidence was found that the analyzed polymorphisms are associated with the IL-6 expression or concentration in patients suffering from BC from Jalisco, Mexico.

Association of the genetic variants (-794 CATT5-8 and -173 G > C) of macrophage migration inhibitory factor (MIF) with higher soluble levels of MIF and TNFα in women with breast cancer.

BACKGROUND: Functional variants -173 G > C (rs755622) and -794CATT5-8 (rs5844572) MIF gene have been associated with the risk in several types of cancer, as well as with the increase of soluble levels of MIF and TNFα. However, in previous studies contradictory and uncertain results have been presented on the implication of MIF polymorphisms with the association in cancer, specifically in breast cancer (BC). We investigated whether the variants are associated with the susceptibility to develop BC and the soluble levels of MIF and TNFα in women with BC from western Mexico. MATERIALS AND METHODS: A total of 152 women with BC and 182 control subjects (CS) were enrolled in this study. The determination of genotypes -173 G > C and -794 CATT5-8 MIF polymorphisms was performed by PCR-RFLP and PCR, respectively. In addition, the soluble levels of MIF and TNFα in both studied groups were quantified by ELISA and MILLIPLEX assay, respectively. RESULTS: The most frequent allele found in BC was the G (74.3%) and 6 (54%) in the variants -173G > C and -794 CATT5-8 , respectively, without significant differences in both groups. Nevertheless, the women with BC carriers -173*C and -794CATT7 have higher levels of MIF in comparison with CS. An increase of MIF (BC: 11.1 ng/mL vs CS: 5.2 ng/mL, P < .001) and TNFα (BC: 24.9 ng/mL vs CS: 9.9 pg/mL, P < .001) was found. CONCLUSION: The functional variants of MIF are not genetic susceptibility markers for BC. Nevertheless, the alleles -173*C and -794CATT7 are associated with the increase of MIF circulating in women with BC.

Selective estrogen receptor modulators in the prevention of breast cancer in premenopausal women: a review.

The detection of premenopausal women at high risk of breast cancer is key to chemoprevention. Therapy with selective estrogen receptor modulators (SERMs) induces a significant antiproliferative effect in estrogen receptor (ER) positive breast cancer. This review was designed according the guidelines of the 2009 PRISMA statement. Searching different databases, including PubMed, MedlinePlus, PLoS One, Cochrane Breast Cancer Specialized Register, Clinical Trials.gov and American Society of Clinical Oncology. From 168 records screened, 15 full text articles were assessed for eligibility and only 7 studies met the inclusion criteria. Three of the studies included analyzed changes in Ki-67 expression, revealing weaker expression after treatment with acolbifene and raloxifene (P<0.001). Three studies also analyzed the breast volume by magnetic resonance imagining (MRI) and demonstrate a significant difference after 1 year with raloxifene treatment (P=0.0017). Moreover, a 20% reduction in breast density was observed after a 2-year treatment with tamoxifen in premenopausal women. SERMs reduce the risk of developing breast cancer. The studies reviewed here demonstrate the modulation of Ki-67 expression and changes in breast density, suggesting an important preventive role for this group of drugs in prevention for premenopausal women at high risk of developing breast cancer.

Circulating soluble levels of MIF in women with breast cancer in the molecular subtypes: relationship with Th17 cytokine profile.

Breast cancer (BC) is a health problem worldwide; there is evidence that inflammatory cytokines are increased in BC. Macrophage migration inhibitory factor (MIF) has multiple effects on immune cells, inflammation and cancer. Besides, in previous studies, contradictory and uncertain results have been presented on the implication of Th17 cytokine profile in BC. The aim of this study was to evaluate the plasma levels of MIF and the Th17 cytokine profile in BC and their association with their molecular subtypes and clinical stage. A total of 150 women with BC of Ella Binational Breast Cancer Study and 60 healthy women (HW) were evaluated in cross-sectional study. The molecular subtypes were identified by immunohistochemistry. The plasma levels of MIF were quantified by ELISA and Th17 cytokine profile by multiplex system. MIF and IL-17 were significantly increased in BC versus HW (11.1 vs. 5.2 ng/mL and 14.8 pg/mL vs. 2.5 pg/mL p < 0.001, respectively). Our analysis showed that both MIF and IL-17A were associated with increased risk of breast cancer (OR 3.85 CI 95% 1.98-7.50 and OR 4.51 95% 1.83-11.15, respectively), higher in aggressive subtypes Luminal B, HER2 and TN. Likewise, we observed positive correlation between MIF and IL-17A (p < 0.001). In addition, IL-17E was lower in BC versus HW (p <0.001). Likewise, we observed a positive correlation between MIF and IL-17A (p < 0.001). In conclusion, both MIF and IL-17A were associated with high risk for breast cancer and aggressive molecular subtypes.

Evaluation of psychosocial aspects in participants of cancer genetic counseling.

BACKGROUND: The instrument called "Hospital Anxiety and Depression Scale" (HADS) is frequently used to evaluate anxious and depressive symptomatology in patients who receive Cancer Genetic Counseling (CGC). However, this instrument cannot identify all of the psychosocial factors, such as the antecedents of the patients' emotional states or their concerns. The objective of the present research was to compare cases detected with psychosocial alterations by means of HADS and a Psychological Health Interview (PHI). METHODS: A transversal analytical design was used. One hundred ten participants were included (97.3% females and 2.7% males). The average age was 45 years ±10 years. RESULTS: The PHI identified twice the amount of participants with psychosocial alterations than did HADS, which only detected 43% of these participants. CONCLUSIONS: The results of our study suggest that the PHI should be applied in addition to HADS to identify participants who would require psychological support due to recurrent concerns.

Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast cancer.

BACKGROUND: Dexamethasone has been reported to reduce postoperative symptoms after different surgical procedures. We evaluated the efficacy of preoperative dexamethasone in ameliorating postoperative nausea and vomiting (PONV), and pain after mastectomy. METHODS: In this prospective, double-blind, placebo-controlled study, 70 patients scheduled for mastectomy with axillary lymph node dissection were analyzed after randomization to treatment with 8 mg intravenous dexamethasone (n = 35) or placebo (n = 35). All patients underwent standardized procedures for general anesthesia and surgery. Episodes of PONV and pain score were recorded on a visual analogue scale. Analgesic and antiemetic requirements were also recorded. RESULTS: Demographic and medical variables were similar between groups. The incidence of PONV was lower in the dexamethasone group at the early postoperative evaluation (28.6% vs. 60%; p = 0.02) and at 6 h (17.2% vs. 45.8%; p = 0.03). More patients in the placebo group required additional antiemetic medication (21 vs. 8; p = 0.01). Dexamethasone treatment significantly reduced postoperative pain just after surgery (VAS score, 4.54 ± 1.55 vs. 5.83 ± 2.00; p = 0.004), at 6 h (3.03 ± 1.20 vs. 4.17 ± 1.24; p < 0.0005) and at 12 h (2.09 ± 0.85 vs. 2.54 ± 0.98; p = 0.04). Analgesics were required in more patients of the control group (21 vs. 10; p = 0.008). There were no adverse events, morbidity or mortality. CONCLUSIONS: Preoperative intravenous dexamethasone (8 mg) can significantly reduce the incidence of PONV and pain in patients undergoing mastectomy with axillary dissection for breast cancer. TRIAL REGISTRATION NUMBER: NCT01116713.

Expression profile of BRCA1 and BRCA2 genes in premenopausal Mexican women with breast cancer: clinical and immunohistochemical correlates.

Low BRCA1 gene expression is associated with increased invasiveness and influences the response of breast carcinoma (BC) to chemotherapeutics. However, expression of BRCA1 and BRCA2 genes has not been completely characterized in premenopausal BC. We analyzed the clinical and immunohistochemical correlates of BRCA1 and BRCA2 expression in young BC women. We studied 62 women (mean age 38.8 years) who developed BC before the age of 45 years. BRCA1 and BRCA2 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and that of HER-2 and p53 proteins by immunohistochemistry. Body mass index (BMI) > or = 27 (52%) and a declared family history of BC (26%) were the main risk factors. Ductal infiltrative adenocarcinoma was found in 86% of the cases (tumor size >5 cm in 48%). Disease stages I-IV occurred in 2, 40, 55, and 3%, respectively (73% implicating lymph nodes). Women aged < or = 35 years (24%) had more family history of cervical cancer, stage III/IV disease, HER-2 positivity, and lower BRCA1 expression than older women (P < 0.05). BRCA1 and BRCA2 expression correlated in healthy, but not in tumor tissues (TT). Neither BRCA1 nor BRCA2 expression was associated with tumor histology, differentiation, nodal metastasis or p53 and HER-2 expression. After multivariate analysis, only disease stage explained BRCA1 mRNA levels in the lowest quartile. Premenopausal BC has aggressive clinical and molecular characteristics. Low BRCA1 mRNA expression is associated mainly with younger ages and advanced clinical stage of premenopausal BC. BRCA2 expression is not associated with disease severity in young BC women.