Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

PURPOSE: Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico. METHODS: Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges. RESULTS: Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). CONCLUSION: Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Obstetric and neonatal outcomes following taxane use during pregnancy: a systematic review.

BACKGROUND: The use of taxanes following the first trimester of pregnancy is endorsed by current clinical guidelines. However, evidence regarding their safety in terms of obstetric and neonatal outcomes is limited. METHODS: A comprehensive literature search was performed using the MEDLINE, CENTRAL and Web of Sciences databases from their inception up to 12/16/2022. Eligibility criteria included gestational taxane use, presentation of original findings, and individual case data presented. A descriptive statistical analysis was undertaken. RESULTS: A total of 159 patients treated with taxane-containing regimens during pregnancy were identified, resulting in 162 fetuses exposed in utero. The majority of patients had breast cancer (n = 88; 55.3%) or cervical cancer (n = 45; 28.3%). The most commonly employed taxane was paclitaxel (n = 131; 82.4%). A total of 111 (69.8%) patients were also treated with other cytotoxic drugs during pregnancy, including platinum salts (n = 70; 63.0%) and doxorubicin/cyclophosphamide (n = 20; 18.0%). While most patients received taxanes during the second trimester of pregnancy (n = 79; 70.0%), two were exposed to taxanes in the first trimester. Obstetric outcomes were reported in 105 (66.0%) cases, with the most frequent adverse events being preterm contractions or premature rupture of membranes (n = 12; 11.4%), pre-eclampsia/HELLP syndrome (n = 6; 5.7%), and oligohydramnios/anhydramnios (n = 6; 5.7%). All cases with pregnancy outcome available resulted in live births (n = 132). Overall, 72 (54.5%) neonates were delivered preterm, 40 (30.3%) were classified as small for gestational age (SGA), and 2 (1.5%) had an Apgar score of < 7 at 5 min. Perinatal complications included acute respiratory distress syndrome (n = 14; 10.6%), hyperbilirubinemia (n = 5; 3.8%), and hypoglycemia (n = 2; 1.5%). In addition, 7 (5.3%) cases of congenital malformations were reported. At a median follow-up of 16 months, offspring health status was available for 86 (65.2%), of which 13 (15.1%) had a documented complication, including delayed speech development, recurrent otitis media, and acute myeloid leukemia. CONCLUSIONS: Taxanes appear to be safe following the first trimester of pregnancy, with obstetric and fetal outcomes being similar to those observed in the general obstetric population. Future studies should aim to determine the most effective taxane regimen and dosage for use during gestation, with a specific focus on treatment safety.

Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer.

The presence of BRCA pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared to carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I-III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). The recurrence-free (RFS) and overall survival (OS) were compared according to mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9-12del CNV and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% (95% CI 72.3-84.6%), with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95%CI: 78.7-90.0%), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and non-carriers (100% vs. 78.6% and 84.7%; log-rank p=0.037 and p=0.051, respectively). This study suggests that BRCA1 ex9-12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers.

Molecular Subtype Discordance in a Young Woman with Synchronous Bilateral Breast Cancer: A Case Report.

Molecular subtype discordance in bilateral synchronous breast cancer is a relatively uncommon entity that poses unique therapeutic challenges. Here we report the case of a 35-year-old woman who presented to our clinic with synchronous bilateral breast cancer (SBBC), with stage IIA triple-negative disease in the right breast and a stage IIB hormone-sensitive tumor in the left breast. She was treated with bilateral modified radical mastectomy and axillary node dissection followed by adjuvant chemotherapy, radiotherapy, and a five-year regimen with daily tamoxifen. To date, the patient remains asymptomatic and free of disease recurrence 78 months after initiating treatment. Little is known about SBBC with a discordant molecular subtype and reports about this entity are scarce. Future studies aimed at identifying the optimal management strategy for this disease are needed.

Factores de riesgo modificables del cáncer de mama: una comparación entre mujeres menores y mayores de 40 años / Modifiable risk factors for breast cancer: a comparison between women younger and older than 40 years-old

Resumen OBJETIVO: Analizar la repercusión diferencial de los principales factores de riesgo modificables asociados con el cáncer de mama en pacientes menores y mayores de 40 años. MATERIALES Y MÉTODOS: Estudio de cohorte, retrospectivo, observacional y descriptivo. Se reunió la información de las pacientes con diagnóstico o tratamiento de cáncer de mama atendidas en un centro hospitalario del Noreste de México entre enero de 2016 y diciembre de 2017. La asociación entre las distintas variables y los grupos etarios se determinó con la prueba de la χ2 de Pearson y se consideraron estadísticamente significativos los valores con p < 0.05. RESULTADOS: Se revisaron 524 expedientes clínicos de pacientes con cáncer de mama, con límites de edad entre 22 y 99 y se seleccionaron las menores de 40 años (n = 75) que representaron 14.31% del total de las pacientes atendidas, porcentaje que coincide con la prevalencia de cáncer de mama en mujeres jóvenes reportada en la bibliografía mexicana. Se encontró un efecto similar en el riesgo de padecer cáncer de mama entre ambos grupos con los siguientes factores de riesgo modificables: nuliparidad, tabaquismo, consumo de alcohol, sedentarismo y anticoncepción hormonal. La obesidad (IMC superior a 30) tuvo mayor repercusión en mujeres de más de 40 años. CONCLUSIÓN: La prevalencia de cáncer de mama en las pacientes jóvenes fue del doble de lo reportado en el ámbito internacional. Es necesario el control de peso en mujeres menores de 40 años, que permita reducir la incidencia del cáncer de mama triple negativo en esta población. Asimismo, se recomienda el control de los otros factores de riesgo modificables porque, aunque no parecen afectar significativamente a las mujeres jóvenes, su control tiene una repercusión positiva en la prevención del cáncer de mama en todos los grupos etarios.

Abstract OBJECTIVE: To analyze the differential impact of the main modifiable risk factors associated with breast cancer among patients younger than 40 years of age. MATERIALS AND METHODS: Cohort, retrospective, observational and descriptive study. The information of the patients with diagnosis or treatment of breast cancer treated in a hospital in Northeast Mexico between January 2016 and December 2017 was collected. The association between the different variables and the age groups was determined with the test of Pearson's χ2 and the values p < 0.05 were considered statistically significant. RESULTS: 524 clinical records of patients with breast cancer were reviewed, with age limits between 22 and 99 years. From this group, patients under 40 years of age (n = 75) were selected, representing 14.31% of the total number of patients treated, a percentage that coincides with the prevalence of breast cancer in young women reported in the Mexican literature. A similar impact was found on the risk of breast cancer between both groups with the following modifiable risk factors: nulliparity, smoking, alcohol consumption, sedentary lifestyle and hormonal contraception. Obesity (BMI ≥ 30) had a greater impact on women ≥ 40 years. CONCLUSION: The prevalence of breast cancer in young patients was double what was reported internationally. Weight control is necessary in women under 40 years of age, which allows reducing the incidence of triple negative breast cancer in this population. Likewise, the control of the other modifiable risk factors is recommended because, although they do not seem to significantly affect young women, their control has a positive impact on the prevention of breast cancer in all age groups.

Glucocorticoid-dependent expression of IAP participates in the protection against TNF-mediated cytotoxicity in MCF7 cells.

BACKGROUND: Glucocorticoid receptor (GR) activation has been associated with breast cancer cell survival in vitro. Glucocorticoid (GC)-dependent protection against tumor necrosis factor (TNF)-induced cell death has been well characterized in MCF7 luminal A breast cancer cells. The GR activates a variety of protective mechanisms, such as inhibitors of apoptosis proteins (IAPs). However, the relative contribution of the GR-dependent expression of IAPs in the protection of cell death has not, to our knowledge, been evaluated. METHODS: MCF7 cells were used for all experiments. GR was activated with cortisol (CORT) or dexamethasone (DEX) and inhibited with mifepristone (RU486). Cell viability was determined in real-time with the xCELLigence™ RTCA System and at specific endpoints using crystal violet stain. The mRNA levels of the eight members of the IAP family were measured by qRT-PCR. The protein levels of GR, PR, ERα, HER2, PARP1, c-IAP1 and XIAP were evaluated by Western blot analysis. The knockdown of c-IAP1 and XIAP was accomplished via transient transfection with specific siRNAs. GR activation was verified by a gene reporter assay. Via the cBioportal interphase we queried the mRNA levels of GR and IAPs in breast cancer tumors. RESULTS: RU486 significantly inhibited the anti-cytotoxic effect of both GCs. PARP1 processing was diminished in the presence of both GCs. The combined treatments of GCs + TNF increased the relative mRNA levels of Survivin>c-IAP1 > NAIP>Apollon>XIAP>Ts-IAP > ML-IAP > c-IAP2. Additionally, GR mRNA content increased with the combined treatments of GCs + TNF. Sustained levels of the proteins c-IAP1 and XIAP were observed after 48 h of the combined treatments with GCs + TNF. With c-IAP1 and XIAP gene silencing, the GC-mediated protection was diminished. In the breast tumor samples, the GR mRNA was coexpressed with Apollon and XIAP with a Pearson coefficient greater than 0.3. CONCLUSIONS: The effect of GCs against TNF-mediated cytotoxicity involves increased mRNA expression and sustained protein levels of c-IAP1 and XIAP. The antagonist effects of RU486 and the qRT-PCR results also suggest the role of the GR in this process. This finding may have clinical implications because the GR and IAPs are expressed in breast tumor samples.

HPLC Method for Quantification of Caffeine and Its Three Major Metabolites in Human Plasma Using Fetal Bovine Serum Matrix to Evaluate Prenatal Drug Exposure.

Caffeine is recognized as the first-line therapeutic agent for apnea of prematurity. The dosage regimen is 10 mg/kg loading dose and 2.5 mg/kg maintenance dose. However, the plasma concentration achieved, not always, is therapeutically useful. It makes necessary to increase the doses to reach plasma concentration up to 30 or 35 µg/mL or even higher to attain therapeutic effect. To study why neonates have these differences, and whether these effects are linked to prenatal caffeine exposure, we had to develop an analytical method for an accurate measurement of caffeine and metabolites concentration. The analysis was carried out using fetal bovine serum (FBS) as biological matrix in a high-performance liquid chromatography with an ultraviolet detector method. This method allows acceptable chromatographic resolution between analytes in 15 minutes. It was validated and proved to be linear in the 0.1-40 µg/mL range for caffeine, paraxanthine, theobromine, and theophylline in the same chromatographic analysis. Accuracy for quality control samples for intra- and interday assays was ranged from 96.5 to 105.2% and 97.1 to 106.2%. Precision had CV no more than 10% in all concentration levels for all analytes. No differences were observed between quantification in human and FBS. This method was applied to quantify plasma drug concentration in mothers and their newborns in a Mexican northeast population. In our study, we confirmed self-reported caffeine maternal intake in 85.2% (n=23); meanwhile, in their newborn's plasma, it was detected only in 78% (n=21). Caffeine plasma concentrations in mother and newborn had a linear relationship, and no differences were observed between groups (mothers versus children). These results suggest that our analytical method and substitution of biological matrix was linear, precise, and accurate for caffeine quantification and could be used for measuring prenatal exposure and let us to study, in the future, concentration differences observed during apnea clinical treatment.