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CDK4/6 inhibitors in breast cancer

Breast cancer

Read time: 60 mins
Last updated:7th Jun 2023
Published:21st Apr 2021

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.

National ranking of cancer as a cause of death at ages <70 years in 2020

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).

Most common type of cancer incidence in women in 2020 by country

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

Most common type of cancer mortality in women in 2020 by

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 stratification3,7

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.

Advanced breast cancer

Advanced breast cancer (ABC) includes inoperable LABC and mBC4.

ABC is largely an incurable disease, with a median overall survival (OS) of approximately 3 years and a 5-year survival rate of roughly 25%4. Survival is strongly associated with BC subtype, with major advances observed in human epidermal growth factor receptor 2-positive (HER2+) ABC4.

Despite being incurable, ABC is a manageable disease. However, the impact of available therapies on survival and quality of life (QoL) of ABC patients has been slow and different, compared with recurrent ABC, with recurrent ABC which is harder to manage4.

Outcomes for patients with ABC are associated with access to the best available care, which includes the best available medicines, multidisciplinary, specialised care, implementation of guidelines, high-quality pathology, imaging and radiotherapy (RT).

Mortality rates for ABC have decreased in the majority of higher HDI countries; most ABC-related deaths occur in less developed countries, and access issues partly account for many of these inequalities4.

Learn clinical trial data on CDK4/6 inhibitors in managing advanced breast cancer

Breast cancer pathophysiology

BC is a heterogeneous disease clinically classified by immunohistochemical (IHC) staining of three receptors:

  • oestrogen receptor (ER)
  • progesterone receptor (PR)
  • human epidermal growth factor receptor 2 (HER2)

Studies conducted in the early 2000s demonstrated that gene expression signatures could classify BC into distinct and reproducible molecular subgroups (Table 1)12–14.

Table 1. Classification of breast cancer on the basis of receptor expression profile (Adapted from Makki et al.12; Tungsukruthai et al.13; Cardoso et al.14).

ER, oestrogen receptor; HER2, human epidermal growth factor receptor-2; Ki-67, proliferation marker protein Ki-67; PR, progesterone receptor.
Molecular subtype Expression profile
Luminal-type A ER+ and/or PR+, HER2-
Luminal-type B ER+ and/or PR+, HER2+ or HER2- and high Ki-67
HER2-enriched ER-, PR-, HER2+
Triple-negative/basal-like ER-, PR-, HER2-

Luminal A-like tumours are typically low grade, strongly ER+/PR+, HER2- and have low proliferative fraction. Luminal B-like tumours are ER+, but may have variable degrees of ER/PR expression, are higher grade and have higher proliferative fraction4.

Given the heterogeneity of breast cancer and the different molecular drivers, treatment needs to be tailored to the individual and the characteristics of their condition

The importance of assessing the expression profiles for HER2 and HR, such as ER or PR, is shown by the fact that they can be both prognostic and predictive of therapy response15.

In our next section, we discuss more about the clinical assessment of breast cancer risk

Hormone receptors and breast cancer progression

The majority of BCs are hormone receptor positive (HR+). This means that ≥1% of tumour cells have positive nuclear staining for ER and/or PR via immunohistochemistry (IHC)16. A cut-off of 1% is used, as patients with even these low levels may benefit from hormonal therapy17. The increase in hormone receptor expression commonly observed in BC cells suggests a switch from paracrine to autocrine signalling by steroid hormones18-20.

Concerns have been raised, however, on the benefit of endocrine therapy for tumours with 1–10% ER expression, termed ‘ER‐low positive’21,22. This subgroup accounts for 2–3% of all ER-positive tumours and is less responsive to endocrine therapy than ER-high positive tumours21,22. The data regarding the efficacy and benefit of endocrine therapy for ER-low-positive BC is limited, 21,22.

Concerns have been raised, however, on the benefit of endocrine therapy for tumours with 1–10% ER expression, termed ‘ER‐low positive’21,22. This subgroup accounts for 2–3% of all ER-positive tumours and is less responsive to endocrine therapy than ER-high positive tumours21,22. The data regarding the efficacy and benefit of endocrine therapy for ER-low-positive BC is limited, but suggests possible benefit, so patients are still considered eligible. There are data to suggest that invasive ER-low positive cancers exhibit behaviour and gene profiles more similar to ER-negative cancers, making it critical that molecular and genetic tools are used to accurately assess the molecular nature of ER-low positive tumours and the optimal treatment strategy for this subgroup21,22.

Interestingly, the expression of ERα, the predominant form of the receptor in the mammary epithelium, is frequently maintained in mBC, and is still expressed in 65–70% of distant metastases23. Signalling via ERα has been shown to promote cell proliferation, survival, migration and epithelial-mesenchymal transition—all key factors in the development of many cancers (Figure 4)23.

Nuclear and extranuclear actions of ERα signalling in breast cancer

Figure 4. Nuclear and extranuclear actions of ERα signalling in breast cancer (Adapted from Saha Roy & Vadlamudi23). EMT, epithelial-mesenchymal transition; ER, oestrogen receptor; MMP, matrix metalloproteinases.

Triple-negative breast cancer (TNBC) lacks ERα and PR, and has few (if any) HER2 receptors; however, expression of ERβ and G protein-coupled oestrogen receptor 1 (GPER-1) triggers oestrogen-responsivity in BC24. Oestrogen signalling in TNBC can also be activated and modulated by oestrogen-related receptors (ERRs). TNBC, therefore, may be responsive to oestrogen through ERα-independent pathways24.

ER-positive (ER+) BC can recur beyond 5 years, and before 5 years, from diagnosis7. Clinical and genomic expression models can help stratify these patients for risk of late recurrence7.

The signalling pathways activated as a consequence of elevated PR levels are less well defined.

Progesterone has been observed to stimulate mammary stem cells and promote cell proliferation resulting in a hypothesis that progesterone signalling plays a role in the progression of EBC25.

However, its role appears to be context dependent. Where it may play a role in the early stages of BC, in breast carcinoma, it can antagonise oestrogen signalling and its presence is associated with favourable prognosis, less aggressive cancer and better overall survival26.

HER2 and breast cancer progression

HER2 is a proto-oncogene encoding a transmembrane tyrosine kinase growth factor that is a member of the epidermal growth factor receptor (EGFR) family. Approximately 20% of breast cancers are positive for HER2, with assessment usually by IHC, although fluorescent in situ hybridisation (FISH) can be used when IHC is equivocal17,27.

Activation and dimerisation of the HER2 receptor with another member of the HER family of receptors results in activation of intracellular signalling pathways promoting cell proliferation, growth, survival and motility (Figure 5)28.

HER2 activation and signalling in breast cancer

Figure 5. HER2 activation and signalling in breast cancer (Adapted28). 611 CTF, 611 carboxy-terminal fragment; AKT, protein kinase B; HER1, 2 or 3, human epidermal growth factor receptor 1, 2 or 3; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Progression of triple-negative breast cancer

TNBC, without the characteristic ERα, PR and/or HER2 expression of most (80–85%) BCs, is a complex and aggressive subtype that causes a disproportionate number of deaths (~25%)29,30.

TNBCs are more likely than non-TNBCs to metastasise within 5 years of diagnosis, while the median time to death and overall survival are also worse31,32.

Gene expression profiling of TNBC has helped characterise four subtypes (basal-like-1, basal-like-2, luminal androgen receptor and mesenchymal)5. However, significant molecular heterogeneity is observed within these subtypes and each of the four subtypes has been observed to co-occur within a single tumour33,34.

Review

  • In 2020, breast cancer in women accounted for an estimated 2.3 million new cases1
  • Incidence of breast cancer in women is influenced by reproductive, hormonal, lifestyle risk factors, and improved mammographic screening1
  • Early breast cancer is confined to the breast, without distant metastatic disease, and with or without regional lymph node involvement3
  • Advanced breast cancer is inoperable locally advanced breast cancer and metastatic breast cancer, and is manageable, but incurable4
  • Oestrogen or progesterone receptors can be prognostic of therapy response3,4
  • Gene expression profiling of triple-negative breast cancer has described some subtypes of breast cancer5

Approximately one-third of patients with early breast cancer progress to metastatic breast cancer1. Risk of cancer recurrence is high in patients with hormone receptor positive early breast cancer1

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