Anti-tumour TreatmentCDK4/6 inhibitors: A focus on biomarkers of response and post-treatment therapeutic strategies in hormone receptor-positive HER2-negative breast cancer
Introduction
Approximately 70% of breast cancers (BC) are hormone receptor (HR)-positive and are reliant on estrogen receptor (ER) signaling for cell proliferation and growth. Endocrine treatments, including aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs), have formed a mainstay of therapy for patients with HR+ and HER2 negative (HR+/HER2neg) BC [1]. Currently, in metastatic breast cancer (MBC), endocrine therapy (ET) is increasingly administered in combination with inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i), given the impressive results of landmark phase III clinical trials [2], [3], [4], [5], [6], [7], [8], [9], [10]. Briefly, PALOMA-1 and PALOMA-2, MONALEESA-2 and MONARCH-3 investigated the addition of CDK4/6i to AIs in patients not previously treated for MBC [2], [3], [7], [8]. PALOMA-3, MONALEESA-3 and MONARCH-2 investigated the addition of CDK4/6i to fulvestrant mostly in patients progressed on a previous line of ET [4], [6], [9], [11]. MONALEESA-7 demonstrated the efficacy of ribociclib plus ET in premenopausal women [5], [10]. Collectively, these studies demonstrated that the addition of CDK4/6i to AIs or fulvestrant in the first-line and second-line settings led to prolonged progression free survival (PFS) and in some instances, overall survival (OS) [12], [13], [14] compared to ET alone, leading to a change in clinical practice in the management of MBC. There is also some evidence in favor of CDK4/6i as monotherapy. MONARCH-1 assessed single-agent abemaciclib in women with refractory HR+/HER2neg MBC [5]. TREnd randomized patients with endocrine-resistant BC to receive palbociclib alone or in combination to the ET upon which their disease progressed in the previous line [15]. In the neoadjuvant setting, NeoPalAna and neoMONARCH assessed the anti-proliferative activity of palbociclib and abemaciclib, respectively, in primary BC [11], [16]. The results of PENELOPE-B (NCT01864746), which examines patients with high-risk early BC with residual disease following neoadjuvant therapy, are anticipated. A recent efficacy and futility analysis of PALLAS (NCT02513394), a multicentre Phase III trial comparing palbociclib plus adjuvant ET versus adjuvant ET alone, suggested it was unlikely to demonstrate a significant improvement in the primary endpoint of invasive disease-free survival (IDFS) [17]. Contrastingly, the Phase III monarchE study (NCT03155997) demonstrated a statistically significant improvement in IDFS for adjuvant abemaciclib plus ET versus ET alone in high-risk, node-positive early disease [18].
Fig. 1 schematically illustrates the complex axis involving CDK4/6 that leads to the progression of cell cycle from G1 to S phase. CDK4 and 6 bind to the D-type cyclins and phosphorylate and inactivate the retinoblastoma protein (Rb). This event allows the transcription factors E2Fs to be released and to bind to DNA, promoting the expression of genes necessary for S phase entry [19]. In HR+ BC, estrogen is one of the proliferative stimuli that activate this axis; ER mediates cyclin D1 expression and thus the subsequent formation of the cyclin-CDK complex [20]. The CDK4/6 pathway is often deregulated in HR+ BC, due to the amplification of CCND1 gene and/or the over-expression of cyclin D1 protein, with Rb usually being retained [21]. These characteristics make CDK4/6 a logical therapeutic target for treating patients with HR+ BC.
Despite significant survival gains via CDK4/6i therapy for patients with HR+/HER2neg MBC, approximately 15% of those patients with CDK4/6i plus an AI, and up to 30% of those treated with CDK4/6i plus fulvestrant, will develop recurrent disease within six months, denoting de novo resistance. Additionally, virtually all patients with MBC will eventually develop progressive disease due to acquired resistance. Mechanisms of resistance are complex, and still poorly understood in terms of underlying biological processes [22], [23]. Many pathways, including growth factor signaling, the Hippo signaling pathway and the immune system have been implicated in CDK4/6i resistance (Fig. 1). Within these pathways, potential biomarkers of de novo and acquired resistance and therapeutic targets to overcome it have been identified.
Here we will review the recent advancements in biomarkers discovery for CDK4/6i and the potential therapeutic strategies after progression on CDK4/6i in HR+/HER2neg MBC. An overview of the seminal clinical trials investigating CDK4/6i in HR+/HER2neg BC that included translational studies as described in this review is reported in Table 1.
Section snippets
Genomic alterations
Genomic alterations have been largely investigated for their association with CDK4/6i response, both in clinical trials and in retrospective cohorts. The majority of the studies have been performed on circulating tumor DNA (ctDNA), a fraction of cell-free DNA found in the blood of patients with cancer [24].
PIK3CA and ESR1 are among the most commonly mutated genes in HR+/HER2neg, endocrine-resistant MBC [25]. Hence studies have focused on the associations between alterations in these genes and
Acquired resistance and subsequent therapies
In MBC, acquired resistance to CDK4/6 inhibitors occurs as a near-inevitability, and patients thereby require further treatment in subsequent lines.
Data from clinical trials [12], [13], [14], [58], [59] and real-world treatment strategies [60], [61], [62] show the most common treatments after progression on CDK4/6i include chemotherapy or ET, as monotherapy or combined with targeted agents (most commonly the mTOR inhibitor everolimus).
A schematic view of the median duration of subsequent lines
Conclusions
Despite remarkable and concentrated efforts to identify potential genomic drivers of de novo CDK4/6i resistance, to date none of these markers demonstrated clinical utility. While the majority of expression data seems to point to a role of cyclin E1 and the E2F pathway in CDK4/6i response, the collective data are still not concordant. Circulating biomarkers are promising, but require further validation. Current therapeutic strategies after progression on CDK4/6i include chemotherapy and ET,
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [I Migliaccio, M Bonechi, A McCartney, C Guarducci: None. M Benelli: Consultant honoraria: Novartis. L Biganzoli: Personal financial interests (honoraria, consulting or advisory role): AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, Pierre Fabre, Roche, Takeda. Institutional financial interests: Celgene, Genomic
Acknowledgements
This work was supported by Fondazione AIRC per la ricerca sul cancro (IG 22869 and MFAG 18880 to L Malorni and MFAG 14371 to I Migliaccio) and Pfizer via an Investigator Initiated Research Grant (to L Malorni) sponsored by “Fondazione Sandro Pitigliani per la lotta contro i tumori” ONLUS. A McCartney is supported by the Fondazione Sandro Pitigliani. This work was also supported by a grant from the Breast Cancer Research Foundation (grant number BCRF 19-037).
Author contribution
Conception and design of the study/ acquisition of data/ analysis and interpretation of data: I Migliaccio, M Bonechi, A McCartney, L Malorni. Drafting and revising the article: I Migliaccio, M Bonechi, L Malorni. Revising the article critically for important intellectual content: A McCartney, C Guarducci, M Benelli, L Biganzoli, A Di Leo. Final approval of the version to be submitted: all authors.
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