“…The TRINITI-1 trial with advanced HR+/HER2− BC with a triplet-therapy (ribociclib plus everolimus plus exemestane) demonstrated clinical benefit at week 24 in 41.1% patients, exceeding the predefined primary endpoint threshold (>10%) [37]. The presence of PIK3CA mutations in liquid biopsy correlated with shorter PFS (7.44 vs. 12.9 months) in patients receiving CDK4/6 inhibitor plus hormone therapy treatment [38]. Taken together, it is worth perusing clinical trials with triple combinations (CDK4/6 inhibitors plus alpelisib or everolimus plus antiestrogen) in a neoadjuvant setting to improve pCR with HR+/HER2−/PIK3CA-mutated BC patients.…”
Section: Pi3k Pathway Inhibitors and Endocrine Therapymentioning
confidence: 99%
“…Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the HR+/HER2− BC treatment landscape. Putative mechanisms of resistance to CDK4/6 inhibitors have been identified, but limited data are available on PI3K deregulation [38]. Dysregulation of the PI3K pathway, including PIK3CA, PTEN, and AKT kinase, leads to an increase in cell proliferation and survival following the disruption of apoptosis.…”
Section: Pi3k Pathway Inhibitors and Endocrine Therapymentioning
A strong association of pCR (pathological complete response) with disease-free survival or overall survival is clinically desirable. The association of pCR with disease-free survival or overall survival in ER+/HER2−breast cancers following neoadjuvant systemic therapy (NAT) or neoadjuvant endocrine therapy (NET) is relatively low as compared to the other two subtypes of breast cancers, namely triple-negative and HER2+ amplified. On the bright side, a neoadjuvant model offers a potential opportunity to explore the efficacy of novel therapies and the associated genomic alterations, thus providing a rare personalized insight into the tumor’s biology and the tumor cells’ response to the drug. Several decades of research have taught us that the disease’s biology is a critical factor determining the tumor cells’ response to any therapy and hence the final outcome of the disease. Here we propose two scenarios wherein apoptosis can be induced in ER+/HER2− breast cancers expressing wild type TP53 and RB genes following combinations of BCL2 inhibitor, MDM2 inhibitor, and cell-cycle inhibitor. The suggested combinations are contextual and based on the current understanding of the cell signaling in the ER+/HER2− breast cancers. The two combinations of drugs are (1) BCL2 inhibitor plus a cell-cycle inhibitor, which can prime the tumor cells for apoptosis, and (2) BCL2 inhibitor plus an MDM2 inhibitor.
“…The TRINITI-1 trial with advanced HR+/HER2− BC with a triplet-therapy (ribociclib plus everolimus plus exemestane) demonstrated clinical benefit at week 24 in 41.1% patients, exceeding the predefined primary endpoint threshold (>10%) [37]. The presence of PIK3CA mutations in liquid biopsy correlated with shorter PFS (7.44 vs. 12.9 months) in patients receiving CDK4/6 inhibitor plus hormone therapy treatment [38]. Taken together, it is worth perusing clinical trials with triple combinations (CDK4/6 inhibitors plus alpelisib or everolimus plus antiestrogen) in a neoadjuvant setting to improve pCR with HR+/HER2−/PIK3CA-mutated BC patients.…”
Section: Pi3k Pathway Inhibitors and Endocrine Therapymentioning
confidence: 99%
“…Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the HR+/HER2− BC treatment landscape. Putative mechanisms of resistance to CDK4/6 inhibitors have been identified, but limited data are available on PI3K deregulation [38]. Dysregulation of the PI3K pathway, including PIK3CA, PTEN, and AKT kinase, leads to an increase in cell proliferation and survival following the disruption of apoptosis.…”
Section: Pi3k Pathway Inhibitors and Endocrine Therapymentioning
A strong association of pCR (pathological complete response) with disease-free survival or overall survival is clinically desirable. The association of pCR with disease-free survival or overall survival in ER+/HER2−breast cancers following neoadjuvant systemic therapy (NAT) or neoadjuvant endocrine therapy (NET) is relatively low as compared to the other two subtypes of breast cancers, namely triple-negative and HER2+ amplified. On the bright side, a neoadjuvant model offers a potential opportunity to explore the efficacy of novel therapies and the associated genomic alterations, thus providing a rare personalized insight into the tumor’s biology and the tumor cells’ response to the drug. Several decades of research have taught us that the disease’s biology is a critical factor determining the tumor cells’ response to any therapy and hence the final outcome of the disease. Here we propose two scenarios wherein apoptosis can be induced in ER+/HER2− breast cancers expressing wild type TP53 and RB genes following combinations of BCL2 inhibitor, MDM2 inhibitor, and cell-cycle inhibitor. The suggested combinations are contextual and based on the current understanding of the cell signaling in the ER+/HER2− breast cancers. The two combinations of drugs are (1) BCL2 inhibitor plus a cell-cycle inhibitor, which can prime the tumor cells for apoptosis, and (2) BCL2 inhibitor plus an MDM2 inhibitor.
“…In detail, a recent study demonstrated that patients carrying a PI3K mutation in ctDNA have a shorter PFS to palbociclib/ribociclib compared to non-mutant PI3K patients. Moreover, the PI3K status was strongly associated to Ki67% expression in primary lesions [108]. Resistance to CDK4/6 inhibitors is claiming great attention, and several studies are investigating how liquid biopsy may help in identifying possible biomarkers of resistance, using either ctDNA [109,110] or exosomes [111].…”
Section: Clinical Application Of Liquid Biopsy Breast Cancermentioning
Despite advances in screening and therapeutics cancer continues to be one of the major causes of morbidity and mortality worldwide. The molecular profile of tumor is routinely assessed by surgical or bioptic samples, however, genotyping of tissue has inherent limitations: it represents a single snapshot in time and it is subjected to spatial selection bias owing to tumor heterogeneity. Liquid biopsy has emerged as a novel, non-invasive opportunity of detecting and monitoring cancer in several body fluids instead of tumor tissue. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), RNA (mRNA and microRNA), microvesicles, including exosomes and tumor “educated platelets” were recently identified as a source of genomic information in cancer patients which could reflect all subclones present in primary and metastatic lesions allowing sequential monitoring of disease evolution. In this review, we summarize the currently available information concerning liquid biopsy in breast cancer, colon cancer, lung cancer and melanoma. These promising issues still need to be standardized and harmonized across laboratories, before fully adopting liquid biopsy approaches into clinical practice.
“… 58 Alpelisib was approved by the FDA on the basis of the presence of PIK3CA mutations both on tissue (if available) and on LB. 58 Moreover, some studies have shown that the onset of mutations in the PIK3CA gene may be one of the mechanisms of acquired resistance to hormone or CDK4/6 inhibitor treatments 59 , 60 , 61 ( Figure 4 ). Figure 4 Emerging applications of LB in breast cancer.…”
Section: Lb In Clinical Settings: Current and Emerging Applicationsmentioning
The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts’ opinions, the AIOM–SIAPEC-IAP–SIBIOC–SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.
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