Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer

Abstract

Background Prioritization of breast cancer patients based on the risk of resistance to tamoxifen plays a significant role in personalized therapeutic planning and improving disease course and outcomes. Methods In this work, we demonstrate that a genome-wide pathway-centric computational framework elucidates molecular pathways as markers of tamoxifen resistance in ER+ breast cancer patients. In particular, we associated activity levels of molecular pathways with a wide spectrum of response to tamoxifen, which defined markers of tamoxifen resistance in patients with ER+ breast cancer. Findings We identified five biological pathways as markers of tamoxifen failure and demonstrated their ability to predict the risk of tamoxifen resistance in two independent patient cohorts (Test cohort1: log-rank p-value = 0.02, adjusted HR = 3.11; Test cohort2: log-rank p-value = 0.01, adjusted HR = 4.24). We have shown that these pathways are not markers of aggressiveness and outperform known markers of tamoxifen response. Furthermore, for adoption into clinic, we derived a list of pathway read-out genes and their associated scoring system, which assigns a risk of tamoxifen resistance for new incoming patients. Interpretation We propose that the identified pathways and their read-out genes can be utilized to prioritize patients who would benefit from tamoxifen treatment and patients at risk of tamoxifen resistance that should be offered alternative regimens. Funding This work was supported by the Rutgers SHP Dean's research grant, Rutgers start-up funds, Libyan Ministry of Higher Education and Scientific Research, and Katrina Kehlet Graduate Award from The NJ Chapter of the Healthcare Information Management Systems Society.

Aptamers for Detection and Diagnostics (ADD): Can mobile systems process optical data from aptamer sensors to identify molecules indicating presence of SARS-CoV-2 virus? Should healthcare explore aptamers as drugs for prevention as well as its use as adjuvants with antibodies and vaccines?

“…Hence, genetic 397 stratification of humans in clinical trials is now routine. The efficacy, effectiveness or resistance 398 of the same drug may be quite different between individuals. The latter partially explains the observed variation 399 in immune 400 responses 401 to CoVID-19.…”

Aptamers for Detection and Diagnostics (ADD) is a proposed mobile app acquiring optical data from conjugated quantum nanodots to identify molecules indicating presence of SARS-CoV-2 virus: Why public health and healthcare need smartphone sensors as a platform for early detection and prevention

“…Hence, genetic 381 stratification of humans in clinical trials is now routine. The efficacy, effectiveness or resistance 382 of the same drug may be quite different between individuals. The latter partially explains the observed variation 383 in immune 384 responses 385 to CoVID-19.…”

Aptamers for Detection and Diagnostics (ADD) is a proposed mobile app acquiring optical data from conjugated quantum nanodots to identify molecules indicating presence of SARS-CoV-2 virus: Why public health and healthcare need smartphone sensors as a platform for early detection and prevention

“…Hence, genetic 389 stratification of humans in clinical trials is now routine. The efficacy, effectiveness or resistance 390 of the same drug may be quite different between individuals. The latter partially explains the observed variation 391 in immune 392 responses 393 to CoVID-19.…”