Year: 2024
Type: editorial
Abstract: This editorial distils the key messages and lessons learned from this article collection to identify future directions for advancing breast cancer (BC) care. First, we have reviews addressing two of the most important questions currently in BC therapeutics, how to extend the gains from immunotherapy to luminal cancers, and how to best treat metastatic luminal cancers following progression on CDK4/6 inhibitor therapy. We then explore the potential of modulating ER beta signaling in triple negative BC (TNBC) and finally look at the biological underpinnings of migration and invasion control to identify therapeutic intervention points. First Attalla et al. examine how to optimize the marginal benefits of immune checkpoint inhibitors (ICI) in luminal BC. They explore both how to identify luminal responders to ICIs and discuss how to overcome low responsiveness. With current pathological BC classification, only TNBCs are approved for ICI treatment. However, the authors note that using alternative immune-based transcriptomic classifications dividing BC into immune high, medium and low categories (1) may better encompass all who may benefit including rarer luminal responders. Moving to improving poor luminal responsiveness, observations that tumour-located cytotoxic T cells correlate with benefit suggests therapies improving tumour lymphocyte infiltration could be beneficial. Potential summarized interventions include; agonism of stimulator of interferon genes (STING), reducing immunesuppressive hypoxic conditions through Hypoxia Inducible Factor (HIF) inhibition and suppressing cytokine gene silencing. Direct manipulation of local immunity through introduction of cytokine mRNAs or genetically engineered T-cells and NK-cells is also covered. Finally, the finding that antiestrogens may cause immune activation is discussed in concert with leading to the concept of synergy between anti-estrogens, CDK4/6 inhibitors and ICIs. This segways into the review of Zhou et al who examine resistance to CDK4/6 inhibitors, the current standard-of-care for first line metastatic luminal BC management, a question with expanding relevance as adjuvant usage commences. The authors conclude that resistance through attenuation of cell cycle arrest is uncommon although acquired retinoblastoma protein mutations and CDK 6 over-expression are occasionally implicated. Considering alternate cell cycle entry points, c-myc changes can drive resistance pre-clinically although clinical targeting is difficult. Encouraging pre-clinical results blocking cell cycle entry through CDK2 (2) have lead to development of CDK2 inhibitors. Looking at parallel pathway activation, acquired resistance is linked to AKT and FGFR signaling. Successful trials inhibiting AKT, mTOR and PI3kinase have lead to the recent FDA approval of capivasertib (3) with other agents in confirmatory randomised trials. In contrast early trials of FGFR inhibitors in unselected patients show modest activity and high toxicity with trials refocusing on patients with FGFR1 alteration. Encouraging preclinical data also support androgen receptor (AR) activation in luminal cancers prompting trials evaluating the selective AR modulator enobosarm as monotherapy or with abemaciclib. Moving away from signaling modulation, observed immune modulatory changes with CDK4/6 inhibition (4) intertwine nicely with our first review and intimate synergies with ICIs. Despite the lack of ER- and progesterone receptor, several other nuclear receptors have relevance in TNBC, introducing prospective new therapeutic targets (5) including AR (6), thyroid receptor-β (7) and ERβ, the subject of our final review (Yan et al). The role of ERβ is complex with the authors elucidating the diverse impacts of different splice variants on TNBC biology. ERβ1 has beneficial roles, suppressing oncogenic pathways such as mTOR, TGF-beta, HIF-1a and AR, suppressing epithelial mesenchymal transition (EMT), maintaining oxidative phosphorylation and suppressing cholesterol biosynthesis. In contrast ERβ2, Erβ4 and ERβ5 are oncogenic, enhancing proliferation, invasion, angiogenesis, and EMT through upregulating HIF-1α activity. Although the opposing roles of these variants could make therapeutic targeting difficult ERβ1 has significantly greater affinity for estradiol than other isoforms allowing selective stimulation. Both estradiol and the oral ERβ1 agonist S-equol (8) can inhibit TNBC proliferation and are in clinical trials. Returning to the central theme of tumour immunity in cancer homeostasis, S-equol neoadjuvant treatment also resulted in immune activation in clinical subjects suggesting that manipulating Erβ1 activity could enhance immune targeting (8). Focusing directly on migration and invasion, in our final study Qiu et al dissect the function of migratory surface structures called lamellipodia which are important in invasion with a focus on lamellipodia CD44 overexpression. CD44 is associated with cell adhesion and known to interact with F-actin which is involved in lamellipodia function. They demonstrate that CD44 overexpression drives increased lamellipodia formation with enhanced cell migration and EMT. Mechanistically, PI3K/Akt signaling activation leads to overexpression of tissue type plasminogen activator (tPA) which then interacts with LDL receptor related protein 1 (LRP1) to activate downstream NFκB and drive invasion. This provides opportunity for inhibition of lamellipodia function at several points through blockade of the tPA/LRP1/NFkB signaling cascade. Pre-clinically PI3K/Akt inhibition or knockdown of tPA reduced lamellipodia positive cells and attenuated migration. It is notable that several conceptual therapeutic intersections arise from these outwardly diverse studies. Our initial two reviews independently conclude that synergistic therapeutic value may come from combining CDK4/6 inhibitor blockade with ICI therapy. This concept has already been piloted through the randomised PACE study where numerically increased progression free survival was observed with the addition of avelumab to fulvestrant and palbociclib although confirmation is awaited in a larger study (9). Interestingly, in TNBC estrogenic activation of ERβ1 lead to immune activation in patients (8) suggesting a reverse strategy where estrogen could enhance ICI function in TNBC. The differing prognostic significance of TILs in luminal BC compared to TNBC (10) suggests differing immune populations infiltrate these tumours which may underlie these divergent therapeutic opportunities.Additionally, several areas of cellular oncobiology repeatedly appear, substantially aligning with the classical Hallmarks of Cancer (11). Beyond the evasion of immune destruction discussed above, reprogramming of energy metabolism with the shift from oxidative phosphorylation to glycolysis and the redirection of glycolysis products into cholesterol biosynthesis was a recurring theme. ERβ1 reversed this effect with a consequent increase in oxidative phosphorylation and downregulation of cholesterol biosynthesis. Further, we note that upregulation of cholesterol biosynthesis is a key pathway in CDK4/6i resistance (12) and can also influence the immune microenvironment (13). Finally, invasion and metastasis, including the related process of EMT frequently recurs. It is upregulated in CDK4/6 inhibitor resistance (14) and is also implicated in modulation of immune response (15). CD44, a molecule associated with the EM hybrid state, is convincingly shown by to increase lamellipodiadriven invasion by Qiu et al. Finally, ERβ1 may hold a solution in tumours with a suitable isoform balance having been shown to downregulate HIF-alpha and EMT with consequent reduction in invasion. In summary, these studies point to important synergies between immunotherapy and other signaling pathways with key common cancer behaviours implicated mechanistically that may further guide individualized therapies in the future.
Authors: A. Redfern, V. Agarwal, S. Alahari
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,295
OpenAlex ID: W4392554446