An Overview of the Roles of CDK4/6 Inhibitors in Metastatic Breast Cancer Elderly Patients

Abstract

Breast cancer is the most common type of cancer in women worldwide. Many studies indicate that breast cancer increases in elderly patients (≥70 years) and suggest that the higher cancer mortality in this population relative to that observed in younger women could be related to organ dysfunction, an advanced and delayed diagnosis, and other morbidities. Endocrine therapy (ET) represents the favorite treatment for patients affected by hormone receptor positive (HR+) metastatic breast cancer (MBC). Unfortunately, half of these patients are resistant to ET. In recent years, new therapeutic options, such as orally highly selective inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6), have been widely investigated in patients suffering from MBC with good outcomes. They are able to bypass resistance from hormonal therapy, by restoring hormone sensitivity and by delaying chemotherapeutic agent use. Thus, CDK4/6 inhibitors, combined with hormonal therapy, represent an alternative treatment for MBC. Unfortunately, the elderly population with MBC remains mostly excluded from clinical trials. Moreover, few data on the efficacy, safety, and short and longterm outcomes of therapies based on the combined treatment of ET and CDK4/6 inhibitors are available. This narrative review highlights the use of CDK 4/6 inhibitor-based therapy for MBC in elderly patients and suggests new therapeutic perspectives.

Breast cancer is commonly diagnosed in women and represents the second leading cause of cancer deaths in the United States (1). About 70% of all breast cancer are hormone receptor-positive (HR+). Evidence indicate that breast cancer increases predominantly in elderly patients (≥70 years) and suggest that the higher rate of cancer mortality in this population relative to those observed in younger women could be related to organ dysfunction, an advanced and delayed diagnosis, and other morbidities (2,3). Significant progress has been reached in the management of breast cancer in the elderly population (4), who are still underrepresented in clinical trials (5,6). Breast cancer treatment in older women is not supported by guidelines, probably because the assessment of their potential frailty is not detected routinely (7,8). Unfortunately, principal indications for the treatment of the elderly population are extrapolated from the guidelines used in the studies performed predominantly on the younger population. Specifically, these guidelines don’t include the significant variability in older patients, particularly their co-morbidities, performance status, physiological age, and frailty (9). Thus, it is particularly difficult to determine whether an oncological therapy is safe, well tolerated or has positive effects in older cancer patients.

Endocrine therapy (ET) is the preferred treatment for patients with HR+ metastatic breast cancer (MBC), although half of these patients became resistant to ET over time. To overcome this, new treatments, such as orally highly selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6), have been taken into account and studied in HR+/human epidermal growth factor receptor 2 (HER2) negative breast cancer patients. Specifically, good outcomes have been obtained in studies performed with orally highly selective inhibitors of CDK4/6 (i.e., palbociclib, ribociclib, and abemaciclib) in MBC patients. CDK4/6 inhibitors bypass resistance from hormonal therapy, by restoring hormone sensitivity and by delaying the use of chemotherapeutic agents. Thus, CDK4/6 inhibitors, combined with hormonal therapy, have changed the history of the treatment of MBC (10). Unfortunately, the elderly population with MBC remains excluded from clinical trials. Moreover, few data on the efficacy safety, and short and long-term outcomes of therapies based on the combined treatment of chemotherapy with CDK4/6 inhibitors, are available. Therefore, it is imperative to set up a precise therapy in terms of safety and efficacy. This narrative review highlights the use of CDK 4/6 inhibitor-based therapy for MBC in elderly patients, and sheds light on new therapies. We carried out literature research to find significant publications from 2000 to 2022, by using the PubMed database by inserting the terms: “metastatic breast cancer hormone dependent” and “elderly patients”.

CDK4/6 Pathway and CDK4/6 Inhibitors: Features and Potential Roles in MBC

The CDK4/6–retinoblastoma (RB)1 pathway plays a central role in the modulation of cellular proliferation. To date, the CDK4/6–RB1 pathway is commonly deregulated in cancer cells (11). The cyclin D1–CDK4/6–RB1 complex mediates cell proliferation which, in turn, is regulated by estrogen signaling. Estrogen signaling positively regulates the expression of cyclin D1, thus favoriting CDK4/6 activity in HER2+ breast cancers, causing the hyper-phosphorylation of RB1 and promoting cell cycle progression. It has been proved that the attenuation of the estrogen cascade reduced the formation of CDK–cyclin complex and then arrested the cell cycle in G0 and G1 phases (12-14). Palbociclib, abemaciclib, and ribociclib, are currently the three principal CDK4/6 inhibitors, approved by the FDA, for the treatment of advanced HER2+ and HER2– MBC (14). These drugs are approved by the FDA when they are combined with aromatase inhibitors and with the selective estrogen receptor degrader, fulvestrant, for patients with HER2+ and HER2– MBC. In monotherapy, abemaciclib is also approved in patients with HER2+ and HER2– MBC. To date, these compounds have a selectivity dependent on structural preference for the specialized adenosine triphosphate protein (ATP)-binding pocket of CDK4/6 (15). Nevertheless, CDK4/6 inhibitors are effective in both young and older patients.

The available data for side effects and toxicity seem to be similar in the two populations (16). CDK4/6 inhibitors are well tolerated by treated patients. In the presence of side effects, supportive care measures and dose modification are applied. Primarily neutropenia and hematological toxicities represent common side effects observed in patients treated with palbociclib and ribociclib, compared to those treated with abemaciclib (17). Cytopenia is frequently provoked by CDK4/6 inhibitors and is considered an on-target effect, due to the role of CDK6 in the proliferation of hematological precursors. Chemotherapy induces apoptosis, while CDK4/6 inhibitors have a cytostatic effect by interacting with neutrophil precursors and thus leading to cellular quiescence rapidly replaced when the substances are held (18). To allow the replacement of hematological precursors, palbociclib and ribociclib are administered intermittently (i.e., 21 days on followed by 7 days off). Abemaciclib, which is more selective for CDK4 than CDK6, can be dosed continuously because it is associated with a lower prevalence of hematological toxicities. Abemaciclib causes more gastrointestinal side effects like diarrhea (19). All three CDK4/6 inhibitors represent the principal substrates of the cytochrome P450 3A4 (CYP3A4) enzyme. Their interaction with other drugs is mediated by a modification of the CYP pathway. As a consequence, moderate or strong inhibitors or inducers of CYP3A4 must be avoided for patients treated with these inhibitors (20). Thus, before starting treatment of MBC patients with CDK4/6 inhibitors, it is necessary to know what other drugs these patients are on, to avoid pharmacological interactions.

The Effects of CDK4/6 Inhibitors in the Treatment of Metastatic Breast Cancer: An Update on Clinical Studies

The combination of CDK4/6 inhibitors with ET represents the standard of care for patients with HER- and HER2+ MBC. Compared to endocrine monotherapy, this combination has many positive effects, including higher response rates and progression-free survival (PFS) benefits, thus maintaining or improving patients’ quality of life. CDK4/6 inhibitors can be combined to fulvestrant (in an endocrine-resistant setting) or to an aromatase inhibitor (in a setting of endocrine-sensitive disease) in de novo or recurrent MBC, in first, second, or further lines (18,21-22). Clinical studies conducted on MBC patients treated with CDK4/6 inhibitors have indicated that the elderly population are represented marginally, and that all participants showed an Eastern Cooperative Oncology Group (ECOG) functional status of 0-1 (23). With regards to the adverse effects of CDK4/6 inhibitors, toxicity represents an important issue in the elderly population. The incidence of neutropenia is higher by using palbociclib and ribociclib. Moreover, neutropenia represents the most frequent side effect related to treatment with abemaciclib. In addition, the data available indicate that advanced age is not a criterion for modifying the dosage of any CDK4/6 inhibitor (17). As reported by Stravodimou et al. (24) for novel advanced luminal breast cancers, combinations of endocrine treatment with CDK4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors (for mutant cancers) and mTOR inhibitors, are the principal therapy and many drugs of these classes have been approved.

An interesting study, the American Flatiron study, was conducted by comparing the treatment of MBC patients with letrozole plus palbociclib to letrozole alone. In this study, more than 1400 women were enrolled, with a median age of 66 years. Importantly, 20% of those patients treated with palbociclib were ≥75 years old. PFS and overall survival (OS) were similar in patients >75 years old and younger patients (25). Also, the retrospective American study published by Kish et al. (26) conducted on 763 patients within the elderly population, gave results, in terms of safety, efficacy, and dose reductions, similar to those obtained in the PALOMA-2 and PALOMA-3 trials (27-29). In the European context, the most important real-world data on the elderly population, is reported by the Ηellenic Cooperative Oncology Group (HeCOG), which observed 365 patients treated with ribociclib or palbociclib combined to hormonal therapy (30). The median age was 61 years (range=34-93), and 12% of the patients were ≥75 years old. Similar toxicity was observed in older and younger patients. The PFS of patients ≥75 years was 10.9 months (95% CI=3.1-24.2) when they were treated with a CDK4/6 inhibitor and hormonal therapy as the first line of treatment and 7.5 months (95% CI=4.5-NR) when they received it as the second line or a subsequent line (N=23). The median OS was 24.2 months (95% CI=10.9-24.2) among those treated with this combination as the first line of treatment and has not yet been detected in patients who received this combination as the second or subsequent line. Altogether, these data confirmed that the efficacy and toxicity of CDK4/6 inhibitors are similar to those observed in randomized clinical trials, with the similar outcomes for both elderly and younger patients. Elderly patients with MBC should receive the best available treatment considering the tolerability and efficacy.

Conclusion

In this article, we shed light on the CDK 4/6 inhibitor-based therapy applied to MBC elderly patients. Unfortunately, many patients develop resistance to CDK4-6 inhibitors and hormonal-based therapy. Thus, prognostic and predictor biomarkers should be investigated to discover the reason of this resistance (31). Of note, cell cycle dysregulation promotes tumor growth. Moreover, the deregulation of cyclin-dependent kinases (CDKs) leads to tumor development, including breast cancer (32). Since cyclin D1 (CCND1) amplification, p16 loss, Rb1 loss, estrogen receptor 1 (ESR1) expression loss, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PI3KCA) mutations and high cyclin E expression are involved in many mechanisms underlying the drug-resistance, their expression profiles should be tested in patients to optimize therapy (33). Liquid biopsies should represent a future method to detect an earlier response to treatment, early progression of the disease, and the right treatment optimization. Moreover, the potential side effects of the treatment could be detected earlier, resulting in an improvement of the quality of life and overall survival (34-36).

Palbociclib, ribociclib and abemaciclib are considered safe and effective drugs for the elderly population. All three drugs combined with hormonal treatment, prolonged PFS in elderly and younger patients. Therefore, the dose should not be reduced at the beginning of treatment. The selection of CDK4/6 inhibitor will depend on different factors such as the drug toxicity profile, patient co-morbidities and the possible interactions with other drugs. The principal national and international clinical guidelines support the idea that it is necessary to perform a comprehensive geriatric assessment (CGA), before deciding treatment options. CGA uses functional status through the patient’s current activities of daily living, visual/hearing status, performance status, socioeconomic status, psychological status, comorbidity scores, nutritional status, poly-pharmacy, and cognitive status (3). Moreover, treatment of MBC is considered palliative care, therefore, the maintenance of a good quality of life and the control of the patients’ symptoms represent a priority.

Conflicts of Interest

The Authors have no conflicts of interest.

Authors’ Contributions

C. Pacilio and S. Bimonte: Conceptualization, writing—original draft preparation; S. Bimonte, A. Crispo, C. Pacilio and M. De Laurentis: writing—review and editing; G. Rosati, F. di Rella, F. Nuzzo: language editing. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

This work was sustained by Profit Eli-Lilly, number I3Y-MC-JPCFm. The Authors are grateful to Dr. Alessandra Trocino from the Istituto Nazionale Tumori IRCCS Fondazione Pascale for providing excellent bibliographic service and assistance. We also thank the Italian Ministry of Health.