Prognostic Parameters of Palbociclib in HR+/HER2- Advanced Breast Cancer: A Narrative Review

Abstract

Recent studies have demonstrated that the combination of Cyclin-Dependent Kinase 4/6 Inhibitor (CDK4/6i) and endocrine therapy (ET) is more effective than ET alone and significantly improves progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC). Palbociclib is the first CDK4/6i approved for use, and its clinical advantages have been shown. However, 30% of patients will continue to develop secondary drug resistance. Therefore, exploring the parameters that can predict the efficacy of Palbociclib and developing a clinical prediction model is essential for evaluating the prognosis of patients.

Keywords

breast cancer palbociclib CDK4/6 inhibitor prognostic parameters

Introduction

According to the latest cancer statistics, female breast cancer (BC) has surpassed lung cancer as the most prevalent malignant tumor threatening human health. The number of cases in China is expected to reach 430,000 by 2022.¹ HR + /HER2- BC type has received a lot of attention as the most common subtype of BC, and the current standard treatment for this subtype is Cyclin-Dependent Kinase 4/6 Inhibitor (CDK4/6i) combined with endocrine therapy (ET). Paloma series of studies (Table 1)^2,5 related to Palbociclib have shown that the drug, when combined with ET, can produce clinical benefits and that both aromatase inhibitors (AIs) and fulvestrant can also prolong progression-free survival (PFS) and overall survival (OS) in HR + /HER2- advanced breast cancer (ABC) patients. Meanwhile, Figure 1 exhibits the mechanism of Palbociclib. In the Flatiron real-world study, the efficacy of Palbociclib plus ET in HR + /HER2- ABC was similar to that reported in the Paloma-2 study. In a more heterogeneous population, Palbociclib plus letrozole retained significant advantages in PFS and OS over letrozole alone.⁶ This brings the total effective rate of Palbociclib combined with different AIs reach 60%, with Palbociclib combined with exemestane having the highest total effective rate of 66.7%.⁷ Furthermore, four years after the approval of Palbociclib, the OPEN real-world study found that the total effective rate of Palbociclib in combination with letrozole was 68% and the clinical benefit rate (CBR) was 87%, indicating that Palbociclib combination with letrozole could provide clinical benefit in the real world.^8,9 The ongoing prospective multicentre Polaris study has yielded encouraging results, with no significant adverse effects on quality of life and a real-world PFS of 35.2 months and OS of 53.3 months after first-line treatment with Palbociclib.¹⁰ Even though the number of studies evaluating the efficacy of Palbociclib continues to increase, patients with HR + /HER2- BC have individualized differences in response to Palbociclib. They are at risk of disease progression during treatment. Therefore, few studies can predict the efficacy of Palbociclib in detail. This article summarizes the existing prognostic parameters and organized a table (Table 2).

Figure 1.

Mechanism of palbociclib in HR + /HER2- BC cell.

Table 1.

Historical Clinical Evidence Supporting the Clinical use of Palbociclib in HR + /HER2- BC Patients.

	Registration Trial	Lines	Phase	Patient Numbers	Menstrual status	Treatment	PFS(months)	OS(months)	ORR(%)
Palbociclib	PALOMA-1(NCT00721409)	first	II	165	Post	Letrozole + palbociclib/Letrozole	10.2 versus 20.2	33.3 versus 37.8	33 versus 43
	PALOMA-2(NCT01740427)	first	III	666	Post/Pre	Letrozole + palbociclib/Letrozole	14.5 versus 24.8	46.8 versus 51.8	35 versus 42
	PALOMA-3(NCT01942135)	≥ first	III	521	Post/Pre	Fulvestrant ± palbociclib	4.6 versus 9.5	28 versus 35	11.1 versus 25
	PALOMA-4（NCT02297438）	first	III	340	Post	Letrozole + palbociclib/Letrozole	13.9 versus 21.5	NA	38 versus 43.4

Abbreviation: NA, not available.

Table 2.

Existing Parameters for Predicting the Efficacy of Palbociclib Plus ET Treatment for HR + /HER2- ABC.

	Parameters	Positivity/Negativity	HR(95%CI)Univariate analysis	P value	HR(95%CI)Multivariate analysis	P value	PFS（months）
Hematologic-related prognostic parameters	ANC<4.01 × 10³mm⁻³	+	0.86(0.76-0.96)	.009	0.84(0.71-0.97)	.008	median:24.19
	NLR ≥ 3.0	−	1.50(0.98-2.25)	.059	1.76(1.13-2.69)	.014	median:6.3
	Baseline ALC<1.5 g/L	−	1.71(1.13-2.60)	.0115	1.76(1.03-3.02)	.0399	6 versus 10
	Baseline sTKa ≥ 200Du/L	−	1.76(1.43-2.16)	<.0001	1.72(1.39-2.12)	<.001	11.2 versus 17.3
	LDH>300U/L	−	2.89(1.68-4.67)	<.001	2.58(1.49-4.26)	.0013	median:6.3
Clinically relevant prognostic parameters	Liver metastases(present)	−	——	.007	2.751(0.995-7.606)	.051	13.02 versus 22.98
	First-line treatment with Pal plus ET	+	——	.033	0.616(0.230-1.648)	.335	22.98 versus 15.94
	PR ≥ 20%	+	0.59(0.32-1.08)	.08	——	——	8.5 versus 6.7
	≥ 14% Ki-67	−	1.94(0.95-3.96)	.062	——	——	6.0 versus 10.8
	≥ 30%	−	1.68(1.0-2.84)	.048	——	——	6.0 versus 8.5
	Concomitant use of PPIs	−	5.60(1.98-15.85)	<.001	7.85(2.67-23.05)	<.001	13.04 versus NR
	at 12 weeks RDI <80% at 36 weeks	−	6.8(2.7-17.7)	.0006	5.33(2.07-14.06)	.0007	6.8 versus 17.1
	at 12 weeks RDI <80% at 36 weeks	−	8.6(3.6-NE)	.0703	——	——	8.6 versus NR
Genetically relevant prognostic parameters	Low CCNE1	+	0.85(0.58-1.26)	.0238	——	——	14.1 versus 4.0
	CDK4>5050copies/mL	+	——	.01	——	——	NR versus 6.45
	PLK1>5.35	−	——	——	2.29(1.51-3.48)	.00011	——
	ctDNA D30/baseline >1	−	5.1(1.4-18.3)	.02	——	——	——

Abbreviations: NE, not evaluable; NR, not reach.

Hematologic-Related Prognostic Parameters

Absolute Neutrophil Count (ANC) and Neutrophil-Lymphocyte Ratio (NLR)

Neutrophils have been shown to promote tumor growth and play a pro-angiogenic role by releasing matrix metalloproteinases that promote angiogenesis and play an immunosuppressive role by inhibiting CD8 + T cells.¹¹ Sun et al.¹² studied the relationship between baseline ANC, NLR, and PFS in 165 patients with HR + / HER2- ABC treated with Palbociclib plus ET as first-line therapy. Univariate analysis revealed that ANC was significantly correlated with PFS, implying that the decrease in ANC suggested prolonged PFS. This association remained significant in multivariate analyses after adjustment for age, metastasis site, and ET type. It is estimated that a 1000 mm⁻³ reduction in ANC reduces the risk of disease progression by 15%. Similarly, NLR was significantly associated with PFS in univariate analysis, and an increased NLR was associated with reduced PFS in multivariate analysis, but this difference was not statistically significant. Therefore, NLR may be an independent predictor of Palbociclib, and a high NLR value was associated with a worse prognosis. This trial was more representative of a real-world clinical setting in which Palbociclib is used in combination with ET because it allows the use of all available ET agents. The mechanism of elevated NLR can be explained by the relative decrease of lymphocytes and the relative increase of neutrophils, which causes the balance of cell microenvironment to be broken, and the inflammatory reaction occurs and develops toward the tumor, which leads to poor prognosis. A Japanese study summarized the NLR further and found that when the NLR was ≥3, the time-to-treatment discontinuation (TTD) of Palbociclib was significantly shorter, demonstrating that high NLR would reduce the efficacy of Palbociclib.^13,14

Previous studies have linked higher Palbociclib exposure to an increased risk of neutropenia (OR = 1.28, 95% CI (1.01; 1.64), P = .031), and the probability of developing high-grade neutropenia for patients with Palbociclib concentrations of 61, 74, and 101 ng/mL was 52, 63, and 82%, respectively. Data from clinical trials indicated that a dose reduction or a prolonged pause (>7 days) decreased the toxicity grade or even normalized the neutrophil count. The risk of developing high-grade neutropenia in patients with a Palbociclib concentration of ∼60 ng/mL (approximately the mean value of the PALOMA clinical trials) was estimated to be 51%.^15,16 Therefore, using low-dose drugs is recommended as much as feasible within the scope of drug effect to reduce the incidence of neutropenia.

Absolute Lymphocyte Count (ALC)

Baseline lymphocytopenia is a poor prognostic factor for various types of cancer. On this basis, EMILE et al.¹⁷ retrospectively studied the effect of baseline ALC level before using Palbociclib combined with ET on the efficacy of Palbociclib in 114 HR + /HER2- ABC patients, and the results showed that a decrease in baseline ALC significantly shortened PFS. Similarly, in multivariate analysis, ALC reduction resulted in a shorter PFS and significantly shorter OS. This could be because T cells have an immunomodulatory role, allowing tumor cells to escape immune surveillance by inhibiting the recruitment of T cells. During Palbociclib treatment, lymphocytopenia reflects T-cell dysfunction, limiting the antitumor function and immune response of the cells. Inflammation-induced cell death and decreased thymic function are considered to be the underlying mechanisms causing peripheral blood lymphocytopenia.¹⁸

Serum Thymidine Kinase (sTK)

Thymidine kinase 1 (TK1), an enzyme involved in the DNA salvage pathway, is primarily expressed in dividing cells and reaches its highest level during S-phase.¹⁹ Therefore, it is considered a cell proliferation marker. Meanwhile, TK1, an E2F-dependent gene, exists downstream of the CDK4/6 pathway and is highly expressed in many cancers, including BC, suggesting that it may play a predictive role in the context of CDK4/6i therapy. The serum TK1 activity (TKa) level before treatment has been confirmed to predict the efficacy of Palbociclib combined with ET in HR + /HER2- ABC patients.²⁰ The median PFS was 17 months for those with low sTKa and 7.4 months for those with high, using median sTKa before treatment as the threshold. Additionally, sTKa can predict the PFS of patients after 3 and 6 months of treatment. The PFS rates of patients with high sTKa were 77% and 56%, respectively, while those with low sTKa had a PFS of 92% and 85%, respectively.²¹ Another single-center retrospective ALCINA study (NCT02866149) found that pre-treatment sTKa level was an independent predictor of PFS and OS.²²

Lactate Dehydrogenase (LDH)

The rise in LDH is not only related to tumor progression but also increases lactic acid production, causes local acidosis, lowers the pH of the microenvironment, and thus induces a change in the tumor microenvironment. Odan et al.¹³ studied the relationship between TTD and LDH in 177 HR + /HER2- ABC patients treated with Palbociclib combined with ET and found that high LDH was a poor prognostic factor. LDH > 300 U/L was significantly correlated with short TTD throughout 8.9 months of follow-up.

Clinically Relevant Prognostic Parameters

Liver Metastases and Number of Treatment Lines

Gharib et al.²² retrospectively analyzed the medical records of 60 HR + /HER2-ABC patients treated with Palbociclib combined with letrozole and found that the presence of liver metastasis and the number of tumor treatment lines may be used as prognostic parameters of efficacy. Having liver metastases before treatment increased the risk of disease progression by 2.75 times and shortened the median PFS to 13.02 months versus 22.98 months without liver metastases. Similarly, when Palbociclib was combined with letrozole as first-line therapy, the median PFS of these patients was extended to 22.98 months, compared to 15.94 months with second-line or higher therapy.

Progesterone Receptor (PR) and Ki-67

PR and estrogen receptor (ER) are expressed in mammary epithelial cells; their positivity is associated with low malignancy, good treatment efficacy, and extended survival time in BC. ER, positivity is more clinically significant than PR positivity. Nonetheless, univariate analysis by Gharib et al revealed that the patients expressing both ER and PR had a median PFS of 20.05 months, while patients expressing only ER had a median PFS of 12.99 months. PR expression can be found to prolong PFS,²³ and PR ≥ 20% is also associated with a longer PFS.²⁴ Ki-67 is a cell proliferation antigen mainly used in clinical practice as an indicator of cell growth rate. The growth rate of the tumor can be preliminarily determined by detecting the expression of the Ki-67 antigen in tumor cells. A retrospective study involving 150 patients found that patients with ≥ 14% level of Ki-67 had a 14% shorter disease-free survival rate than those with Ki-67 < 14%. Further analysis showed that patients with Ki-67 ≥ 30% had significantly shorter PFS than those with Ki-67 < 30%.²⁵ Palleschi et al.²⁶ found that when PR and Ki-67 were used as continuous variables, the PFS of patients treated with ET combined with Palbociclib was inversely correlated with Ki-67 expression but not with PR. This suggested that ET combined with Palbociclib has a greater effect on tumor proliferation than PR expression. In contrast, high PR was found to be independently associated with longer PFS, not Ki-67, in other studies exploring the efficacy of the same biomarker treated with first-line ET in combination with Palbociclib.

Proton Pump Inhibitors (PPI）

PPI is a mildly basic drug that has been proven to inhibit the growth of tumor cells and increase the sensitivity of chemotherapy drugs.²⁷ Palbociclib is also a weakly alkaline drug whose solubility depends on pH, and PPIs can increase the pH in the stomach. When the pH increased to 4.5, the solubility of Palbociclib rapidly decreased to less than 0.5 mg/mL, decreasing its blood concentration and efficacy. M. Del Re et al.²⁵ found that using PPI in the process of Palbociclib combined with ET would change PFS. Among 112 HR + /HER2- ABC patients, 50% were treated with Palbociclib and PPI to avoid gastroesophageal reflux disease, while 50% were not. The results showed that patients who received PPI had shorter PFS than those who received Palbociclib combined with ET alone. Multivariate analysis confirmed that co-use of PPI was the only independent predictor of shorter PFS.

Relative Dose Intensity (RDI)

The RDI is the percentage of the actual dose intensity to the standard, and it has been reported to predict the efficacy of Palbociclib combined with AIs as first-line therapy for HR + /HER2- ABC. Analysis of 56 eligible patients after the first 12 weeks of treatment showed dose reduction in 25 patients, with the median PFS of 8 in patients with RDI < 80% being 6.8 months and the median PFS of patients with RDI ≥ 80% being 17.1 months. The probability of disease progression in patients with RDI < 80% was more than four times higher than that of patients with RDI ≥ 80%. By 36 weeks of treatment, the median PFS of patients with RDI < 80% was 8.6 months, and RDI ≥ 80% was not reached. So we concluded that RDI < 80% tends to shorten PFS, although this conclusion needs to be verified by larger studies.²⁸

Genetically Relevant Prognostic Parameters

Cyclin E1 (CCNE1)

The protein Cyclin E, encoded by the CCNE1 gene, is a member of the highly conserved cyclin family. It forms a complex with CDK2 and functions as its regulatory subunit. This complex activity is important for the progression of cell proliferation from the G1 to S phase; it phosphorylates RB, releases E2F, and promotes cell entrance into S-phase, leading to tumor cells proliferation and, in turn, resistance to Palbociclib. Turner Nicholas C et al.²⁹ studied patients with Paloma-3 and found that the efficacy of Palbociclib combined with fulvestrant was lower in patients with high CCNE1 gene expression than in patients with low CCNE1. In preoperative POP trials, high CCNE1 mRNA expression was associated with the antiproliferative activity of low Palbociclib. After adjusting for clinicopathological characteristics at the time of medication, including recurrence type, tumor tissue collection site, visceral metastasis, previous chemotherapy, previous AI therapy, and previous tamoxifen therapy, the effect of CCNE1 mRNA on the efficacy of Palbociclib remained significant. Its predictive value in metastatic tissues was higher than that in primary lesions. In contrast, in patients sensitive to ET in the past, CCNE1 mRNA was usually expressed at low levels, which also indicated that high expression of CCNE1 mRNA is related to Palbociclib resistance.³⁰

CDK4 mRNA

CDK4 is one of the targets of CDK4/6i, and its expression level is related to the efficacy of Palbociclib. A prospective pharmacogenetic clinical study reported a positive association between baseline plasma-derived extracellular CDK4 mRNA and response to treatment with Palbociclib plus fulvestrant treatment. The high plasma CDK4 mRNA level (> 5050 copies/mL) was associated with a better clinical response, whereas a lower baseline ( ≤ 5050 copies/mL) was associated with a shorter median PFS.³¹ However, for CDK6, another CDK4/6i target, the current study only proved that its high expression was related to the efficacy of fulvestrant, and its effect on Palbociclib was unknown.

Polo-Like Kinase 1 (PLK1)

PLK1 is a member of the Polo-like kinase family, a class of serine/threonine kinases widely found in eukaryotic cells. It can interact with various substrates through its kinase activity to regulate cell mitosis, cytokinesis, DNA damage response, and other processes. The PEARL phase III study found that PLK1 gene expression levels correlated with PFS in patients treated with Palbociclib. In multivariate analyses, patients with high pre-treatment PLK1 expression exhibited lower PFS than those with low PLK1 expression after adjusting for age, disease site, metastasis site, Ki-67, and other confounding factors.³¹

Circulating Tumor DNA (ctDNA)

ctDNA is a cell-free form of extracellular DNA found in body fluids such as blood, synovial fluid, and cerebrospinal fluid. It is a characteristic tumor biomarker that plays an important role in diagnosing, treating, and prognosis of tumors. A study collected plasma samples from patients at baseline, on days 15 and 30 to measure ctDNA; the ratio of ctDNA to baseline on these days (D15/baseline, D30/baseline) was used to predict the efficacy of Palbociclib combined with fulvestrant. ctDNA levels were detected in 84% of the 61 patients at baseline, but it was found not to affect PFS. The detection rate of ctDNA at D15 and D30 was 82% and 68%, respectively, but ctDNA detected on D15 was not associated with PFS. Patients without ctDNA detected by D30 had significantly longer PFS than those with ctDNA detected, indicating that D30 ctDNA detection and dynamic changes are prognostic factors for PFS, and D30/baseline ctDNA > 1 predict disease progression after three months.³² Another study examined plasma samples from patients in the Paloma-3 study and found that changes in PIK3CA ctDNA levels can predict PFS after 15 days of cycle 1 treatment with Palbociclib plus fulvestrant. Serial plasma samples were collected at baseline, day 15 of cycle 1, and at progression to assess whether ctDNA could predict the efficacy of Palbociclib. Researchers used the ctDNA ratio (CDR), which represents mutation abundance/baseline, to determine whether ctDNA decreased during treatment. The results showed that the PIK3CA CDR15 was less than 1 in all patients taking Palbociclib at CDR15. This suggested a decrease in PIK3CA ctDNA level during treatment; patients with PIK3CA CDR15 levels higher than the median 0.034 had shorter PFS than those with lower levels; however, baseline PIK3CA ctDNA had no predictive ability.³³

Clinical Prediction Model

The above prognostic parameters are based on a single biomarker to predict disease prognosis, however, the predictive power of a single biomarker is limited and not accurate enough. Therefore, researchers have focused on integrating multiple variables and constructing predictive models to more accurately predict the prognosis of patients. Dandachi et al.³⁴ conducted a prospective study using longitudinal tumor fraction trajectories to predict the risk of PFS events in HR + /HER2- ABC patients receiving CDK4 /6i, including those who exhibited resistance to such inhibitors. Through multiple follow-up visits to HR + /HER2- ABC patients and using the Modified Fast Aneuploid Screening Test-SeqS and PCR techniques to evaluate the somatic cell copy numbers of all chromosomes at each follow-up and substituting into the computational model constructed by the researchers to obtain a genome-wide z-score is called a longitudinal z-score, to replace the tumor fraction in the blood. And determine the correlation between the longitudinal z-score of logarithmic conversion and PFS by using a joint model. Joint model consists of a quadratic mixed growth model with random intercept at patient level and random slope for linear follow-up time for the longitudinal component, a Weibull model for the time-to-event component, a current association specification of the association parameter α and an unstructured variance-covariance matrix. Patient-specific outcome predictions according to z-score trajectories were obtained using the Stata routine stjmcsurv based on the dynamic prediction approach of Rizo poulos. It was found that a single baseline high logz score was not associated with PFS and could not predict clinical outcomes. However, in the joint model, patients with increased logz scores over time have a higher risk of PFS events at any follow-up time (P < .05), which may indicate that patients with increased logz scores over time are more likely to develop resistance to CDK4 /6i. At the same time, the joint model can also provide dynamic prediction for individual patients by recording the z score trajectory at each follow-up, providing a reference for formulating diagnosis and treatment plans. This indicates that a series of longitudinal z-score levels, rather than a single time measurement, are needed to make a statistically significant prediction of the susceptibility of this population to CDK4 /6i resistance. However, this study also has limitations. When somatic copy changes are limited to a few chromosomes, the z score will be lower than the tumor score in the blood. Secondly, this study involves fewer patients and is not suitable for clinical application. In the future, it needs to be supported by a larger sample of research.

Discussion

Paloma 1-4 studies confirmed the efficacy of Palbociclib combined with ET in HR + /HER2- ABC patients. However, most parameters predicting the efficacy of Palbociclib came from retrospective studies, and there was a lack of prospective studies to verify its accuracy further. Until now, only one multicenter, prospective study³⁵ detected a statistically significant increase of serum tumor markers CEA and CA15.3 in patients with progressive disease (PD) treated with CDK4/6i (the majority of patients received Palbociclib as the CDK4/6 inhibitor of choice). In other studies,³⁶ however, there were individual differences, with the proportion of patients showing a correlation between marker elevation and radiologically documented PD ranging between 54% and 80% for CA15.3 and between 30% and 50% for CEA. However, as the sensitivity was not high, they could only be used as a reference index for efficacy prediction. Moreover, the mechanism of action of hematological, clinical, genetic, and other related predictors has not been thoroughly studied, necessitating large-scale experimental exploration.

Even though CDK4 /6i can provide clinical benefits, drug resistance is unavoidable.³⁷ Malignant tumors are prone to natural or acquired resistance to CDK4/6i, which impacts its therapeutic effect and clinical application. According to the findings from preclinical studies, various mechanisms may contribute to CDK4/6i resistance, such as RB1 loss, E2F amplification, mouse double minute 2 homolog overexpression.³⁸ CDK4/6i mediated cell cycle arrest and aging requires a complete cell cycle pathway, so the cell cycle specific mechanism is considered to be the primary factor leading to drug resistance, and the non-specific cell cycle mechanism has also been found to mediate CDK4/6i drug resistance, such as fibroblast growth factor receptor 1 signaling pathway, mitogen-activated protein kinase signaling pathway, among which the PI3 K /AKT /mTOR signal pathway is widely studied.³⁹ Preclinical research using inhibitors targeting its target has yielded encouraging outcomes. At the same time, some recently discovered CDK4/6i mechanisms, such as CDK4/6 targeted therapy, exert an immune regulatory effect on tumor cells and produce a complex immune regulatory network on immune cells in the tumor microenvironment. The role of mechanisms such as CDK4/6i, BC cell apoptosis, and aging in drug resistance remains to be studied. A large number of preclinical studies have provided many possible related factors for the mechanism of CDK4 /6i resistance. Although it provides potential biomarkers for identifying the drug resistance mechanism of CDK4/6i in vitro and in vivo experimental models, however, a single biomarker has a weaker predictive ability for drug resistance to CDK4 /6i compared to multivariate models. This showed that the problem of CDK4/6i drug resistance is not mediated by a single mechanism but is the result of the interaction of multiple mechanisms and that each patient with drug resistance is different. Due to the failure of all efforts to find single markers in clinical research, researchers have focused on drug resistance prediction models that can consider the complex effects of multiple factors. Based on the results of preclinical studies, we believe that different patients have different reasons for developing CDK4/6i resistance. Therefore, in order to serve a population of patients with drug resistance caused by different mechanisms of action, a model emphasizing the synergistic effect of multiple factors is crucial. The development of a clinical prediction model is encouraging. However, most prediction models in published articles are still based on retrospective study data, such as the prediction model constructed by Zhou et al came from The Cancer Genome Atlas (TCGA) database.⁴⁰And there is still a lack of sufficient prospective data to validate them; therefore, the clinical conversion rate remains low. Additionally, some studies attempted to predict efficacy using a mathematical logic model to synthesize many gene expression level data. Although current research in this field is not mature, precision medicine is a promising direction that also requires the participation of interdisciplinary disciplines, such as the mathematical modeling of big genetic data based on artificial intelligence. However, selecting the right patient seems more difficult than expected. Because the existing clinical data are limited to patients treated with CDK4/6i plus ET, this is a rather narrow scenario compared to other cancers with different carcinogenic backgrounds. Future clinical research will benefit from a comprehensive analysis of multiple biomarkers involved in cell cycle regulation or mitotic pathways.

CDK4/6i post-treatment progress is a new clinical dilemma; however, the relevant breast cancer guidelines have not yet given Level I recommendations. This demonstrates a large window of opportunity for CDK4 /6i post-drug resistance research. Furthermore, the research has a significant barrier because most of the tumor tissues analyzed in clinical trials are from primary breast tumor samples rather than actual progressive metastatic disease sites, which has limitations. Moreover, the exploration of drug resistance reversal strategies mainly focuses on the theoretical stage and preclinical research, which requires sufficient clinical trial data to establish reliability and safety. Researchers generally have high expectations for PI3 K /AKT/mTOR triple therapy. However, in the age of precision medicine, each patient with drug resistance may have different mechanisms, making it impossible to solve the problem of CDK4/6i resistance in all patients with a single reverse drug resistance treatment strategy. Combining biomarkers or gene expression levels is necessary for precisely targeted treatment. Additionally, whether to reverse the drug resistance once it happens or to implement the preventive reverse drug resistance strategy in ABC, which entails the difference between primary and acquired drug-resistant patients, is still debatable. Moreover, for any combination of multiple drugs, the adverse reactions caused by the combination are unavoidable, and balancing safety and efficacy becomes a challenge.

Conclusion

This review summarized the existing parameters for predicting the efficacy of palbociclib and briefly describes the clinical prediction model. This review provides theoretical support for the follow-up treatment of HR + /HER2- ABC. But unfortunately, we have not found a single biomarker that can accurately predict the prognosis. Drug resistance is an inevitable outcome, and it is not mediated by a single mechanism, but is the result of the interaction of multiple mechanisms. Precision medicine is a promising direction, and the clinical prediction model is one of the achievements. Future clinical research will benefit from comprehensive analysis of multiple biomarkers involved in cell cycle regulation or hormone and mitotic pathway.

Footnotes

Abbreviations

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article

ORCID iDs

Keyu Chen

Xiaojia Wang

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