The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer-A Review of Molecular Characterisation, Therapeutic Targets and Future Trends.

Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.

Association Between ABCB1 Genetic Variants and Persistent Chemotherapy-Induced Alopecia in Women With Breast Cancer.

Importance: Persistent chemotherapy-induced alopecia (pCIA) has been recently described in patients with breast cancer and in its most severe form occurs in up to 10% of these patients. Genetic risk factors associated with pCIA have not been adequately explored. Objective: To identify genetic variants associated with pCIA. Design, Setting, and Participants: In this genetic association study, 215 women with breast cancer treated with docetaxel-based chemotherapy with a follow-up of 1.5 to 10 years after the end of the treatment were recruited retrospectively through 3 hospital oncology units across Spain between 2005 and 2018. Severe pCIA was defined as lack of scalp hair recovery (Common Terminology Criteria for Adverse Events, version 3.0, grade 2) 18 months or more after the end of treatment. Patients with grade 2 pCIA were selected as cases, and those with no sign of residual alopecia 12 months after the end of docetaxel treatment were selected as controls. A genome-wide association study in a discovery phase was conducted, and logistic regression was used to identify variants associated with the risk to develop this adverse effect. The validity of the association was addressed through a replication phase. Exposures: Docetaxel-based chemotherapy. Main Outcomes and Measures: Genotypes of single-nucleotide variants associated with pCIA. Results: In total, 215 women with breast cancer (median age, 51.6 years; interquartile range, 44-60 years) were recruited (173 patients for the discovery phase and 42 patients for the replication phase). In the discovery phase, ABCB1 genetic variants were associated with risk to develop pCIA. In particular, single-nucleotide variation rs1202179, a regulatory variant located in an enhancer element that interacts with the ABCB1 promoter, was associated with the occurrence of pCIA. This finding was validated in the replication cohort (combined odds ratio, 4.05; 95% CI, 2.46-6.67; P = 3.946 × 10-8). This variant is associated with ABCB1 mRNA expression, and the risk allele was associated with decreased ABCB1 expression levels (P = 1.64 × 10-20). Conclusions and Relevance: This is the first study, to our knowledge, that identifies an association between a regulatory variant in the ABCB1 gene and the occurrence of pCIA in patients with breast cancer who were treated with docetaxel-based therapies. This finding suggests an important insight into the biological mechanisms underlying pCIA and opens the opportunity to explore personalized treatment of these patients.

Prevalencia de la arteria estriada medial distal en una muestra de poblaciones Colombiana y Peruana / Prevalence of distal medial striatal artery in a sample of Colombian and Peruvian populations

La arteria estriada medial distal hace parte de la circulación encefálica, nace de la arteria cerebral anterior generalmente a nivel de la arteria comunicante anterior, aunque según distintos estudios su origen varía, siendo así difícil de determinar con exactitud. Su importancia clínica radica en la prevalencia de aneurismas encontrados en esta arteria, que posteriormente podrían causar complicaciones debido a la región que irrigan, siendo estas las secuelas somático-vitales y neuropsicológicas, además de su inadecuado abordaje quirúrgico sin prever las alteraciones que puedan ser ocasionados; a causa de lo anterior es de vital importancia que los profesionales de la salud tengan previo conocimiento de la anatomía y la prevalencia de esta arteria en la población. Se realizó un estudio observacional de tipo descriptivo en donde se analizó la arteria estriada medial distal en 70 encéfalos, piezas de los anfiteatros de Medicina de la Universidad de Ciencias Aplicadas y Ambientales U.D.C.A. (Bogotá), la Universidad Científica del Sur UCSUR (Lima); fijados en formol al 10 %, se realizaron mediciones morfométricas mediante calibrador digital y se tomó el registro fotográfico con una cámara Canon. Posteriormente se ejecutó el análisis estadístico mediante el programa IBM SPSS Stadistics 24. Se encontró una prevalencia del 88,6 % de al menos una arteria estriada medial distal en población colombiana y un 97,1 % de la población peruana. Se identificó un diámetro externo promedio de 0,64 mm en población colombiana y de 0,68 mm en población peruana. Se observó una longitud promedio de 2,5 cm en ambas poblaciones. Se evidenció el mayor lugar de origen en la porción A2 de la ACA con un 37,1 % de población colombiana y un 51,4 % de población peruana. Se debe conocer adecuadamente la anatomía y las correspondientes variaciones anatómicas de esta arteria para así poder realizar un adecuado abordaje neurológico y neuroquirúrgico.

The distal medial striate artery is part of the brain circulation, born from the anterior cerebral artery generally at the level of the anterior communicating artery, although according to different studies its origin varies, being thus difficult to determine with accuracy. Its clinical importance lies in the prevalence of aneurysms found in this artery, which could later cause complications due to the region they irrigate, these being the somatic-vital and neuropsychological sequelae, in addition to its inadequate surgical approach without foreseeing the alterations that may be caused; Because of the above it is of vital importance that health professionals have prior knowledge of the anatomy and prevalence of this artery in the population. An observational descriptive study was carried out in which the distal medial striated artery in 70 brain cells, pieces from the Medicine amphitheatres of the Universidad de Ciencias Aplicadas y Ambientales U.D.C.A. (Bogotá), the Universidad Científica del Sur UCSUR (Lima); fixed in 10 % formalin, morphometric measurements were made by automatic calibrator and the photographic record was taken with a Canon camera. Subsequently, the statistical analysis was executed through the IBM SPSS Statistics program 24. A prevalence of 88.6 % of at least one distal medial striate artery was found in the Colombian population and 97.1 % of the Peruvian population. An average external diameter of 0.64 mm was identified in the Colombian population and 0.68 mm in the Peruvian population. An average length of 2.5 cm was observed in both populations. The largest place of origin was evidenced in the A2 portion of the ACA with 37.1 % of the Colombian population and 51.4 % of the Peruvian population. The anatomy and the corresponding anatomical variations of this artery must be adequately known to be able to perform an adequate neurological and neurosurgical approach.