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CDK4/6 inhibitors in breast cancer

Breast cancer

Read time: 60 mins
Last updated:13th Apr 2022
Published:22nd Apr 2021

Learn to select the most suitable CDK4/6 inhibitor for your patients with breast cancer.

  • Explain to your colleagues important differences between the three CDK4/6 inhibitors
  • Become an expert in navigating the treatment landscape for early and advanced breast cancer
  • Apply your knowledge to stratify and assess patients on the basis of their risk of recurrence

Early and advanced breast cancer

Cancer is a leading cause of death and a burden to global life expectancy1,2. Breast cancer (BC) in women accounts for 1 in 4 cancer cases, with an estimated 2.3 million new cases in 20201. The increased incidence rates of BC in women reflects reproductive, hormonal, lifestyle risk factors and improved mammographic screening1.

Gene expression and molecular profiles are used to characterise BC subtypes3,4. Progesterone (PR) signalling may play a role in the progression of early breast cancer (EBC)3; oestrogen (ER) or PR receptors can be prognostic of therapy response; ERα is usually maintained in metastatic breast cancer (mBC)4. Gene expression profiling of triple-negative breast cancer (TNBC) has aided in delineating disease subtypes5.

EBC is disease confined to the breast, with or without regional lymph node involvement, and the absence of distant metastatic disease3. Advanced breast cancer (ABC) includes inoperable locally ABC (LABC) and mBC, and is manageable, though incurable, with currently approved treatments4.

Breast cancer epidemiology

Cancer is a leading cause of death and an important barrier to increasing life expectancy in every country of the world1,2. According to the World Health Organization (WHO), cancer is the first or second leading cause of death before the age of 70 years in 112 of 183 countries and ranks third or fourth in a further 23 countries (Figure 1)1,2.

Lilly_T1_CDK46_Fig1.png

Figure 1. National ranking of cancer as a cause of death at ages <70 years in 2020 (Adapted from WHO, 20201).

The increasing prominence of cancer as a leading cause of death partly reflects declines in mortality rates of stroke and coronary heart disease, compared with cancer, in many countries1.

Overall, the burden of cancer incidence and mortality is rapidly growing worldwide. This increase is partly due to ageing and growth of the population, and changes in the prevalence and distribution of the main risk factors for cancer1.

In 2020, breast cancer in women surpassed lung cancer as the leading cause of global cancer incidence, with an estimated 2.3 million new cases, signifying 11.7% of all cancer cases1. It is the fifth leading cause of cancer mortality globally, with 685,000 deaths1.

BC in women accounts for 1 in 4 cancer cases, and for 1 in 6 cancer deaths, ranking first for incidence in 159 countries (Figure 2), and for mortality in 110 countries (Figure 3).

Lilly_T1_CDK46_Fig2.png

Figure 2. Most common type of cancer incidence in women in 2020 by country (Adapted from WHO, 20202).

Lilly_T1_CDK46_Fig3.png

Figure 3. Most common type of cancer mortality in women in 2020 by country (Adapted from WHO, 20202).

Factors responsible for increasing global incidence rates of breast cancer

The increased incidence rates of BC in women in higher Human Development Index (HDI) countries reflects the influence of several factors1:

  • reproductive risk factors (advanced age at first birth, fewer children, less breastfeeding, oral contraceptives)
  • hormonal risk factors (early age at menarche, later age at menopause, menopausal hormone therapy)
  • lifestyle risk factors (alcohol consumption, obesity, physical inactivity)
  • improved cancer detection through organised or opportunistic mammographic screening

Early breast cancer

Early breast cancer (EBC) is confined to the breast, with or without regional lymph node involvement, and the absence of distant metastatic disease3.

This definition is based on several considerations. EBC is potentially curable, whereas inoperable locally advanced breast cancer (LABC) and metastatic breast cancer (mBC) are not.

In top-ranked countries listed in the higher Human Development Index (HDI), more than 80% of patients with EBC have long-term survival following surgery or systemic therapies such as chemotherapy, hormone therapy, targeted therapy, or local radiation. By contrast, patients with LABC and mBC are rarely long-term survivors3.

Approximately 30% of patients with EBC progress to mBC. For hormone receptor-positive (HR+) EBC, a common breast cancer subtype, risk of recurrence is high, even in patients with longer disease-free periods (>5 years) following endocrine therapy (ET)6–8.

Prognostic biomarkers can help identify risk (high/low) and type (early/late) of recurrence in EBC patients, and recently developed risk stratification tools can now assess both clinicopathological and molecular properties of EBC7–11.

Learn more about risk stratification tools for patients at high-risk of cancer recurrence in section 3, ‘Breast cancer stratification’3,7.

In terms of novel treatments for EBC, ongoing clinical trials are assessing cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6 inhibitors) in the adjuvant setting for HR+/human epidermal growth factor receptor 2-negative (HER2-) EBC.

Watch Professor Stephen Johnston discuss the role of CDK4/6 inhibitors in high-risk HR+/HER2- EBC in our CME and eLearning section

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Breast cancer risk

Women at high risk of breast cancer (BC) are those with3,8,32:

  • a strong family history of breast, ovarian or pancreatic cancer
  • diagnosis of BC before the age of 50 years
  • diagnosis of triple-negative breast cancer (TNBC) before the age of 60 years
  • personal history of ovarian cancer or second BC

Phenotypic markers that identify people who carry pathogenic mutations that increase the risk of BC are not currently known. A family history evaluation is therefore necessary to assess the risk of predisposing genes for BC in a family3,32.

More than 90% of patients with BC are diagnosed with early-stage disease, of whom approximately 70% have cancers that are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-)14.

Although many patients with HR+/HER2- BC will not have recurrence, or distant recurrence on standard adjuvant endocrine therapy (ET), up to 20% of patients may have recurrence in the first 10 years, often with distant metastases, at which time the disease is incurable33.

For those patients with high-risk clinical and/or pathological features, risk of recurrence is higher, especially during the first few years on adjuvant ET34.

It is therefore critical to optimise risk assessment and adjuvant therapy to prevent early recurrences and metastases3. This section focuses on current tools and approaches used in BC risk assessment.

Assessment of breast cancer risk

Healthcare professionals may assess BC risk using these approaches3,8,32:

  • Identify patients at risk of a germline mutation and offer them formal genetic testing
  • For patients who do not meet the criteria for genetic testing, or who test negative for germline mutations, quantify the risk of developing cancer over a specified length of time

With the resulting assessment information, surveillance or lifestyle, pharmacological or surgical interventions can be administered to improve a patient’s risk profile (Figure 6)32.

Lilly_T3_CDK46_Fig1.png

Figure 6. Assessment in women at risk of breast cancer (Adapted from Amir et al.32).

BC risk is multifactorial. Hence, optimal risk assessment of BC involves consideration of clinicopathological, molecular and genetic factors.

Risk assessment of breast cancer: clinicopathological factors

Important clinicopathological factors used in BC risk assessment are3,4:

  • expression of ER/PR, HER2 and proliferation markers, such as Ki-67
  • number of involved regional lymph nodes
  • tumour histology
  • tumour stage (tumour size, presence of peritumoural vascular invasion)
  • histological grade

Immunohistochemically detected tumour markers are incorporated into the eighth edition of the American Joint Committee on Cancer (AJCC) Tumour, Node, Metastasis (TNM) to improve risk assessment, which also uses genomic assays to downstage some ER+, lymph node-negative tumours3,4.

As asymptomatic distant metastases are rare, comprehensive laboratory testing, including tumour markers and radiological staging, is not necessary for all patients. Minimum blood work-up, including a full blood count, liver and renal function tests, alkaline phosphatase and calcium levels, is advised before surgery and systemic (neo)adjuvant therapy3.

In patients at higher risk of BC—high tumour burden, aggressive biology, signs, symptoms or laboratory values suggesting the presence of metastases—imaging of chest, abdomen and bone is recommended. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scanning may be useful when conventional methods are inconclusive, and may replace traditional imaging for staging in high-risk patients3.

At a general level, clinicopathological parameters can fail to characterise the biological heterogeneity of tumours, which has important implications for treatment benefit. Traditional clinicopathological-based adjuvant chemotherapy (ChT) may not permit accurate individualised treatment. ChT overexposure is possible in low-risk groups, or in those who are already cured, and it can limit optimal treatment planning for groups at high risk of recurrence7.

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Breast cancer stratification

Breast cancer (BC) can be stratified into different entities on the basis of clinical behaviour, histological features, and/or by biological properties. As current anticancer agents target biological mechanisms, detailed molecular stratification is a requirement for clinical management of breast BC3,4.

Assays for risk stratification focus on prediction of the response to existing treatment regimens. Gene-expression profiling shows that BCs can be stratified in so-called intrinsic subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like and normal-like), which mostly corresponds to hormone receptor (HR) and HER2 status, and further stratifies luminal tumours on the basis of proliferation12–14.

Stratification is critical for selecting patients with BC who could benefit from adjuvant therapy3,4,7. This is especially important for patients with early breast cancer (EBC), who comprise the majority of patients, because of widespread uptake of screening mammography3,4,7.

Stratification could also be important for selecting patients for clinical trials. It could facilitate the discovery of novel drivers, the study of tumour evolution, and the identification of mechanisms of treatment resistance.

While only 6–10% of the women are diagnosed with de novo metastatic breast cancer (mBC), most women with mBC have been previously diagnosed with locally advanced disease and subsequently have cancer recurrence in the form of metastasis6. Approximately 30% of these patients will develop incurable cancer recurrence6–8.

Risk of cancer recurrence is high in patients with hormone receptor-positive (HR+) and oestrogen receptor-positive (ER+) BC. Relapse of BC may occur as late as >20 years after the initial diagnosis, particularly in patients with ER/progesterone receptor-positive (PR+) BC3.

The higher the risk of cancer recurrence, the more aggressive the therapy. Thus, stratification can prevent chemotherapeutic overtreatment in some patients at low risk of recurrence, or in those who are cured, and it can enable planning suitable treatments or prevention strategies in those at high risk of recurrence3,7.

A clinical decision-making tool has been proposed for the combined use of clinical and genomic tests for risk stratification of patients upon completion of 5 years of endocrine therapy (ET) without distant recurrence (Figure 7)7.

Lilly_T2_CDK46_Fig1.png

Figure 7. Decision-making aid for clinical and genomic testing (Adapted from Richman & Dowsett et al.7). BCI, Breast Cancer Index; CTS5, Clinical Treatment Score at 5 Years; PAM50, Prediction Analysis of Microarray 50; EPClin, EndoPredict®.

In Figure 7, the clinical treatment score at 5 years (CTS5) is calculated for all women upon completion of 5 years of adjuvant ET. For most women with a low CTS5 score, ET can be discontinued because extended therapy is unlikely to benefit them. For most women with a high risk of recurrence, extended ET up to 10 years is recommended if the toxicity profile is favourable. In both situations, genomic testing is unlikely to add further prognostic information and is not recommended. Women with an intermediate clinical risk and those at borderline low-intermediate or high-intermediate clinical risk should receive a genomic test to enable integrated clinical-genomic stratification of their risk of late recurrence. Following genomic testing, the following scenarios are possible: discontinuation of ET for patients with a low risk of recurrence or recommendation of extended ET for up to 10 years in patients with a high risk. Women who remain at an intermediate level of risk should discuss toxicities and personal preferences with their clinician.

Role of hormone receptors and biomarkers in breast cancer stratification

Oestrogen receptor

ER is arguably the most important prognostic biomarker in BC, because of the development of targeted therapy with tamoxifen or aromatase inhibitors.

The application of 5 years of adjuvant tamoxifen-based therapy in ER+ BC showed a 29% reduction of the risk for death from the disease33,64,65. In approximately 30–40% of patients with advanced ER+ BC, response to the treatment is likely to be positive. In approximately 20% of patients, stable disease could be achieved. Hormone therapy is generally free of toxicity, permitting long-lasting use66.

Progesterone receptor

In EBC, PR expression is associated with tumour grade, ER expression, Nottingham prognostic group and HER2- status67. Evidence shows a better prognosis in PR+ cancers67. The evaluation of PR expression does not appear to have a role in the ET choice in both locally advanced and mBC68.

PR is expressed in 60–70% of invasive ductal carcinomas. The correlation between ER and PR expression is high, but 10% of ER+ cancer can be PR-. In these patients, the risk of recurrence and mortality compared to ER+/PR+ cancer are higher69.

High expression of PR protein is more frequently observed in tumours with a better baseline prognosis (luminal A) than in tumours with a poor baseline prognosis (luminal B).

Ki-67

No significant relationship between proliferation index (Ki-67) and prognostic factors such as hormone receptors and HER2 has been found66. Furthermore, no significant correlation was observed between Ki-67 and disease-free survival (DFS) at 3 and 5 years or with overall survival (OS) at 5 years70. Therefore, the role of Ki-67 in patient stratification is limited.

Although Ki-67 may be used to discriminate higher risk groups in the context of ER+/PR+ BC, no consensus has been agreed on the cut-off66.

HER2

HER2+ is more frequently found in ER- cancers than in ER+ tumours. Only 12 % of ER+ BCs are positive for HER2 by amplification/overexpression of the gene71.

Tumours with HER2 amplification are associated with a less favourable prognosis when compared with tumours having similar morphological features, but lacking amplification of the gene or the overexpression of the protein66.

Although HER2 was originally proposed as a prognostic biomarker for BC, currently its usefulness lies in predicting response to anti-HER2 therapy in neoadjuvant and adjuvant settings66.

Amplification/overexpression of HER2 is a necessary condition for the administration of anti-HER2 therapies. Of the anti-HER2 treatments available, trastuzumab is the most studied.

Although hormone receptors and HER2 overexpression currently represent the main protagonists of targeted therapy for BC, chemotherapy (ChT) remains the standard of care for tumours lacking ER, PR and HER2 expression. Consequently, much effort in BC research involves study of targetable molecules with predictive purposes in triple negative tumours66.

Triple-negative breast cancer

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Breast cancer treatment landscape

Treatment of breast cancer (BC) in specialised breast units or centres, defined as specialised institutions or departments that care for a high volume of BC patients, improves disease-free survival (DFS) and overall survival (OS), daily functioning, and quality of life (QoL)3,4.

Treatment in these units/centres is provided by a multidisciplinary team (MDT) specialised in BC. MDTs provide “consistent, continuous, co-ordinated, and cost-effective care to the patient,”80 and there is evidence to suggest that decisions made by an MDT are more likely to align with evidence-based guidelines81–84. Introduction of multidisciplinary care has been shown to significantly improve outcomes such as mortality85.  

BC MDTs consist of medical oncologists, breast surgeons, radiation oncologists, breast radiologists, breast pathologists and breast nurses. A breast nurse, or a similarly trained and specialised health care practitioner, usually acts as a “patient navigator.” Patients ought to be actively involved in all management decisions3,4.

Treatment options for early breast cancer

Treatment of EBC is complex and involves multiple options. These include local modalities (surgery, radiotherapy (RT)], systemic anticancer treatments (chemotherapy [ChT], endocrine therapy [ET], molecularly targeted therapies) and supportive measures, delivered in diverse sequences3.

Prognostic and predictive biomarkers such as oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and approved genomic signatures can help determine suitable treatments (Figure 8)3.

Lilly_T4_CDK46_Fig1.png

Figure 8. Early breast cancer treatment algorithm (Adapted from Cardoso et al.3). BCS, breast-conserving surgery; ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; RT, radiotherapy; TNBC, triple-negative breast cancer. To view levels of evidence and grades of recommendation, see Table 2.

Surgery

Table 4 provides an overview of current local surgical treatments for EBC3.

Table 4. An overview of current local surgical treatments for early breast cancer (Adapted from Cardoso et al.4).

Local treatment Recommendation
Breast-conserving surgery (BCS) · BCS is the preferred local treatment for many patients with EBC, with the use of oncoplastic techniques, to maintain good cosmetic outcomes in certain patients, when needed.
Mastectomy · Besides simple mastectomy and skin-sparing mastectomy (SSM) that preserves the skin envelope, nipple-sparing mastectomy (NSM) has been increasingly used in the last decade

· Breast reconstruction should be available and proposed to all women requiring mastectomy
Risk-reducing mastectomy · Risk-reducing surgery (with prophylactic bilateral mastectomy and reconstruction) may be offered to women at very high risk, such as BRCA1 or BRCA2 mutation carriers. or those who have had previous chest RT at young age
Sentinel lymph node biopsy (SLNB) · SLNB, rather than full nodal clearance, is the standard-of-care for axillary staging in early, clinically node-negative BC
Radiotherapy (RT) · Postoperative RT is recommended after BCS

· Boost RT is advised to reduce the risk of in-breast relapse in patients at higher risk of local recurrence
Accelerated partial-breast RT after BCS (APBI) · APBI is an acceptable treatment in patients at low risk for local recurrence
Post-mastectomy RT (PMRT) · PMRT is recommended for high-risk patients

Adjuvant systemic treatment

The decision on adjuvant/neoadjuvant systemic treatment is based on the predicted patient sensitivity to particular treatment types, the benefit from their use, and the patient’s risk of relapse (Figure 9)3. Relapse relies on the patient’s tumour burden and tumour biology.

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CDK4/6 inhibitor overview

Many breast cancers (BCs) are diagnosed at an early stage. These tumours are mostly hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) and are sensitive to endocrine therapies (ETs). However, approximately 20% of patients have cancer recurrence, usually as incurable metastatic disease, despite such treatment130. Ongoing efforts to improve survival in this subgroup include the development of new endocrine agents or extended duration of ET.

HR+/HER2- BC cells often overexpress cyclin D, which activates cell cycle progression through cyclin-dependent kinases 4 and 6 (CDK4/6). Therefore, HR+/HER2- BC cells are sensitive to CDK4/6 inhibitors, such as oral abemaciclib, palbociclib and ribociclib130.

The combination of CDK4/6 inhibitors with endocrine therapy (ET) has been used successfully in the treatment of HR+/HER2- advanced breast cancer (ABC), showing significantly longer progression-free survival (PFS) and overall survival(OS)87,127–139.

Watch this video from our roundtable discussion with leading BC experts on the most interesting data related to CDK4/6 inhibitors for managing BC.


Learn clinical trial outcomes and the latest progression-free survival and safety data in advanced breast cancer for CDK4/6 inhibitors

In this section, we focus on the role of CDK4 and CDK6 in the regulation of the cell cycle, BC pathogenesis, and the mode of action for these CDK4/6 inhibitors in BC.  

CDK4/6 pathway

CDK4/6 and cell proliferation

The mammalian cell cycle is a tightly regulated, ordered process that is active through four distinct phases termed G1, S, G2 and M (Figure 11)139.

Lil_CDK46_Fig3.png

Figure 11. The classical model of the mammalian cell cycle (Adapted from Malumbres & Barbacid139). CDK 1,2,4 or 6, cyclin dependent kinase 1,2,4 or 6; G1, gap 1 phase; G2, gap 2 phase; M, mitosis; S, DNA synthesis.

Between each phase is a controlled checkpoint that is regulated by cyclins and cyclin-dependent kinases (CDKs)139. Cyclin-dependent kinases (CDKs) belong to a family of serine/threonine protein kinases that interact with specific cyclins to promote cell cycle progression (as well as other functions). Cyclins are a diverse family of proteins divided into four classes (A, B, D and E) with multiple members within each class, such as cyclin D1, D2 and D3.

The role of CDK4/6 in the cell cycle

During the G1 phase of the cell cycle, cells must overcome the restriction point, which is a checkpoint that, once passed, commits a cell to the S phase and another cycle of cell division139. Progression through G1 and the restriction point requires synthesis of cyclin D and the formation of a cyclin D:CDK4/6 complex139. A key function of the cyclin D:CDK4/6 complex is to overcome the inhibitory function of the retinoblastoma (RB) protein that binds and sequesters the transcription factor E2F139.

Cyclin D:CDK4/6 complexes phosphorylate RB reducing its ability to bind E2F and enabling E2F to drive the transcription of genes required for the S phase of the cell cycle (Figure 12)140,141. These include cyclin E, which binds CDK2 and promotes progress through the S phase and genes involved in DNA replication.

CyclinD:CDK4 has been shown to directly promote other pathways involved in cell proliferation, migration and the DNA damage response, while CDK6 may play a kinase-independent role in angiogenesis142,140.

Lil_CDK46_Fig4.png

Figure 12. The role of cyclin D:CDK4/6 in breast cell proliferation (Adapted from Finn et al.140). CDK, cyclin-dependent kinase; E2; oestrogen; E2F, E2 factor; ER, oestrogen receptor; HER, human epidermal growth factor receptor; P, phosphorylation; RB, retinoblastoma protein.

Role of CDK4/6 in breast cancer pathogenesis

Escape of senescence and progression through the cell cycle is essential for cancer development and progression. A number of strategies are utilised by BC cells to achieve this, many resulting in an increase in cyclin D-dependent activity140.

Amplification of CDK4 and cyclin D1 has been observed in 15–25% of BCs, while overexpression of cyclin D1 has been reported in over half of all BCs140. Interestingly, amplification of cyclin D1 and CDK4 genes differs between BC subtypes. Cyclin D1 amplification was seen in 29%, 58% and 38% of luminal A, luminal B and HER2 subtypes, respectively140. Meanwhile, CDK4 amplification was seen in 14%, 25% and 24% of luminal A, luminal B and HER2 subtypes, respectively140. However, reduced expression/mutation/loss of Rb protein is more common in the basal subtype where changes in cyclin D and CDK4 were less common140.

Upstream signalling is also capable of driving increased cyclin D:CDK4/6 activity. Oestrogen activation of ER upregulates cyclin D1 levels culminating in increased activation of CDK4/6 and cell proliferation140. Mitogenic signalling pathways can also promote cyclin D1:CDK4/6 signalling.

Interestingly, cyclin D1 can independently activate ER suggesting a possible mechanism for ER+ cells becoming resistant to hormone therapy and the oestrogen-independence of some ER+ cancers140.

CDK4/6 inhibition

For many years, it was believed that the cyclins and CDKs would be essential to cellular proliferation and normal embryonic development. However, this changed with the discovery that knockout mice lacking individual cyclins or CDKs were viable and double knockouts of CDK4/6 and triple knockouts of cyclin D1, D2 and D3 develop normally until mid-late gestation140.

Further, BC cells that become oestrogen-independent and resistant to hormone therapy are still reliant on cyclin D:CDK4/6 signalling to drive proliferation140,143.

With these insights and the likelihood that CDK4/6 may be dispensable for some normal cell function, in addition to existing knowledge on inhibiting kinase activity, CDK4/6 became an increasingly interesting target for drug discovery140.

Many of the initial attempts at CDK inhibition resulted in poor activity and an undesirable adverse event profile. These first generation of CDK inhibitors, including flavopiridol and UCN-01, were essentially pan-CDK inhibitors140,142. Following the poor outcomes associated with pan-CDK inhibition, second generation CDK-specific inhibitors were developed.

While CDK2 was an initial target for many groups looking to develop inhibitors, the focus shifted to inhibition of CDK4/6. In recent years, the first CDK inhibitors targeting CDK4/6, have reached the market (Figure 13)142.

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