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Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard of care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression of phosphorylation of the retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both tumor and stromal compartments, which serve to explain aspects of their clinical activity. Here, we review these phenomena and discuss how they might be leveraged in the development of novel CDK4/6 inhibitor-containing combination treatments. We also briefly review the various known mechanisms of acquired resistance in the clinical setting.

The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)–retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes.

Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1–21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7–25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9–12·6) and group C (5·7 months, 5·4–7·0; HR 0·67 [95% CI 0·45–1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2–7·2) and group C (HR 0·94 [0·64–1·38]; p=0·77). The most common grade 3–4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. Eli Lilly and Company.

Although the role of TGF-ß in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-ß blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTßRII, a soluble TGF-ß type II receptor) and pharmacologie (1D11, a TGF-ß neutralizing antibody) approaches to block TGF-ß signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-ß blockade significantly decreased tumor growth and metastasis. TGF-ß blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-ß blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-ß blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent leading to better control of tumor growth.

Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P= 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610,P= 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465,P= 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs.

Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT. Specifically, the skipping of FLNB exon 30 induced EMT by releasing the FOXC1 transcription factor. Moreover, skipping of FLNB exon 30 is strongly associated with EMT gene signatures in basal-like breast cancer patient samples. These observations identify a specific dysregulation of splicing, which regulates tumor cell plasticity and is frequently observed in human cancer. As the human body develops, countless cells change from one state into another. Two important cell states are known as epithelial and mesenchymal. Cells in the epithelial state tend to be tightly connected and form barriers, like skin cells. Mesenchymal state cells are loosely organized, move around more and make up connective tissues. Some cells alternate between these states via an epithelial-to-mesenchymal transition (EMT for short) and back again. Without this transition, certain organs would not develop and wounds would not heal. Yet, cancer cells also use this transition to spread to distant sites of the body. Such cancers are often the most aggressive, and therefore the most deadly. The epithelial-to-mesenchymal transition is dynamically regulated in a reversible manner. For example, the genes for some proteins might only be active in the epithelial state and further reinforce this state by turning on other ‘epithelial genes’. Alternatively, there might be differences in the processing of mRNA molecules – the intermediate molecules between DNA and protein – that result in the production of different proteins in epithelial and mesenchymal cells. Li, Choi et al. wanted to know which of the thousands of human genes can endow epithelial state cells with mesenchymal characteristics. A better understanding of the switch could help to prevent cancers undergoing an epithelial-to-mesenchymal transition. From a large-scale experiment in human breast cancer cells, Li, Choi et al. found that a group of proteins that bind and modify mRNA molecules are important for the epithelial-to-mesenchymal transition. Two proteins in particular promoted the transition, most likely by binding to the mRNA of a third protein called FLNB and removing a small piece of it. FLNB normally works to prevent the epithelial-to-mesenchymal transition, but the smaller protein encoded by the shorter mRNA promoted the transition by turning on ‘mesenchymal genes’. This switching between different FLNB proteins happens in some of the more aggressive breast cancers, which also contain mesenchymal cells. Finding out which FLNB protein is made in a given cancer may provide an indication of its aggressiveness. Also, looking for drugs that can target the mRNA-binding proteins or FLNB may one day lead to new treatments for some of the most aggressive breast cancers.

In mouse models of patient-derived breast cancer brain metastases, combined inhibition of PI3K and mTOR resulted in regression, and therapeutic response was correlated with a reduction in 4EBP1 phosphorylation. Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Background The enhanced knowledge of cancer biology has led to considerable advancement in systemic therapy for advanced breast cancer. Recently, studies showed that cyclin-dependent kinase (CDK) 4/6 inhibitor, when added to endocrine therapy, had improved the outcomes of patients with advanced ER-positive HER2-negative breast cancer. However, the disease often progresses following a period of treatment response. In a subset of patients, disease progression may occur at limited sites, i.e., oligoprogressive disease (OPD). In the past few years, stereotactic radiotherapy (SRT) has emerged as a safe and effective treatment for advanced cancer when delivered to limited metastatic sites. Hence, it is worth investigating the role of SRT in the setting of oligoprogressive breast cancer. Method AVATAR is a multicentre phase II registry trial of SRT with endocrine therapy and CDK 4/6 inhibitor for the management of advanced ER-positive HER2-negative breast cancer. The study aims to enrol 32 patients with OPD limited to 5 lesions. The primary endpoint of the study is time to change systemic therapy measured from the commencement of SRT to change in systemic therapy. Secondary objectives include overall survival, progression free survival and treatment related toxicity. The exploratory objective is to describe the time to change in systemic therapy by the site (bone only vs. non-bone lesions) and number (1 vs. > 1) of OPD. Discussion This study aims to explore the effect of SRT in maximising the benefit of systemic therapy in patients with oligoprogressive ER-positive HER2-negative breast cancer. This approach might help reduce the burden of disease and improve the life quality in these patients. Trial registration ACTRN, ACTRN12620001212943 . Date of registration 16 November 2020- Retrospectively registered.

Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg ( n  = 3), 400 mg ( n  = 3), 500 mg ( n  = 3), and 600 mg ( n  = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1.