ABSTRACT
Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient's tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor identified several therapeutic choices, including Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient's CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient's CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.
ABSTRACT
Introducción Si bien el cáncer de mama hereditario representa entre el 5-10% del total de los cánceres de mama, es importante la detección de pacientes portadoras de mutaciones patogénicas en genes brca1/2 y otros genes relacionados con el cáncer de mama ya que esta información permitirá tomar conductas adecuadas de prevención y/o tratamiento tanto en la paciente portadora como en sus familiares. Objetivo Llevar a cabo un análisis retrospectivo de 106 pacientes que realizaron estudios genéticos para genes brca1/2 y otros genes relacionados con el cáncer de mama. Resultados Del total de 106 pacientes, encontramos: 17 (16,03%) con mutación patogénica; 38 (35,85%) con vus (Variantes de significado incierto) informadas en el reporte original; y 51 (48,11%) con estudios negativos. De los 38 informes con vus, 7 (6,6%) fueron reclasificadas como vus verdaderas a junio de 2018. De las 17 mutaciones patogénicas encontradas, 16 correspondieron a mutaciones en los genes brca1/2 (15,09%) y 1 a mutación en el chek2 (3,77%). Conclusiones Los estudios genéticos de predisposición en cáncer de mama son, en la actualidad, una herramienta fundamental para la atención multidisciplinaria de la paciente de alto riesgo en un consultorio de patología mamaria. Es un deber del mastólogo pensar en la indicación de un estudio genético de predisposición al cáncer de mama y derivar al genetista para identificar correctamente al paciente que se va a beneficiar de esta información
Introduction Although hereditary breast cáncer represents 5-10% of all breast cancers, it is important to detect patients carrying pathogenic mutations in brca1/2 genes and other genes related to breast cáncer as this information will allow take appropriate prevention and / or treatment behaviors in both the patient carrier and their family members. Objective To make a retrospective analysis of 106 patients who carried out genetic studies for brca1/2 genes and other genes related to breast cancer. Results From 106 patients we found 17 (16.03%) with pathogenic mutations, 38 (35.85%) with vus (variant of unknown significance) in the original report, and 51 (48.11%) negatives. From 35 vus, we reclasified as true vus only 7 (6,6%) in June 2018. From 17 pathogenic mutations in 106 patients studied (16.03%), we found 16 in the brca1/2 genes (15.09%) and 1 mutation in chek2 (3.77%). Conclusions Genetic predisposition tests in breast cáncer are a fundamental tool for multidisciplinary care of the high-risk patient in a breast center query. The mastologist has to think in the first place about the indication of a genetic testing ofbreast cancer predisposition, and refer to the geneticist for a prompt consultation for patients benefit
Subject(s)
Breast Neoplasms , Genetic Predisposition to Disease , GenesABSTRACT
Personalizada, Predictiva y Preventiva. En una medicina de la era posgenómica que vira hacia el paradigma de las 3P, los biobancos emergen como una necesidad de muestras de muy alta calidad para las nuevas tecnologías de secuenciación genética de última generación a gran escala, como los next generation sequencers.
Subject(s)
Breast Neoplasms , Genomics , Human Genome ProjectABSTRACT
PURPOSE: ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome. EXPERIMENTAL DESIGN: We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively. RESULTS: Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group. CONCLUSIONS: Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/physiopathology , DNA Methylation , Promoter Regions, Genetic/genetics , Receptors, Progesterone/metabolism , Adult , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Female , Gene Expression Regulation, Neoplastic/genetics , Gene Order , Humans , Middle Aged , Prognosis , Protein Isoforms/metabolism , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Survival Analysis , Tamoxifen/therapeutic use , Treatment OutcomeABSTRACT
In cancer, epigenetic changes such as covalent addition of methyl groups to the genomic DNA itself are more prominent than genetic changes. Cytosine-phosphate-guanosine (CpG) methylation negatively affects gene transcription of an adjacent gene. It is thought that DNA methylation significantly contributes to all hallmarks of cancer. Next to being a potential therapy target, DNA methylation is an emerging field of biomarkers. Technically, DNA provides a stable and robust analyte that is particularly suitable for clinical applications. Moreover, there are numerous potential human DNA sources that could facilitate integration of methylation tests in clinical practice. In breast cancer, DNA methylation has shown promise as a potential biomarker for early detection, therapy monitoring, assessment of prognosis or prediction of therapy response. In particular, paired-like homeodomain transcription factor 2 (PITX2) DNA methylation has been validated using a robust assay for paraffin-embedded tissue for clinically relevant outcome prediction in early breast cancer patients treated by adjuvant tamoxifen therapy.
