51 research outputs found
Publisher Correction: Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI (Nature Medicine, (2022), 28, 5, (924-933), 10.1038/s41591-022-01772-9)
In the version of this article initially published, a list of the DECIDE-AI expert group members and their affiliations was omitted and has now been included in the HTML and PDF versions of the article. *A list of authors and their affiliations appears online
HER2-family signalling mechanisms, clinical implications and targeting in breast cancer.
Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC
Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention
The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in
malignant transformation, prevention of apoptosis, drug resistance and
metastasis. The expression of this pathway is frequently altered in
breast cancer due to mutations at or aberrant expression of: HER2,
ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other
oncogenes and tumor suppressor genes. In some breast cancer cases,
mutations at certain components of this pathway (e.g., PIK3CA) are
associated with a better prognosis than breast cancers lacking these
mutations. The expression of this pathway and upstream HER2 has been
associated with breast cancer initiating cells (CICs) and in some cases
resistance to treatment. The anti-diabetes drug metformin can suppress
the growth of breast CICs and herceptin-resistant HER2+ cells. This
review will discuss the importance of the
EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but
will also include relevant examples from other cancer types. The
targeting of this pathway will be discussed as well as clinical trials
with novel small molecule inhibitors. The targeting of the hormone
receptor, HER2 and EGFR1 in breast cancer will be reviewed in
association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3
pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for
Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di
Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della
Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT
{[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian
Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB
{[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research,
(AIRC) (RM PI); Italian Association for Cancer Research, (AIRC)
{[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli
Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials
Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient\u27s optimal therapy is a challenge, where oncologists must select a therapy with the highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool-risk groups developed by the National Cancer Center Network (NCCN)-our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization
- …