Breast cancer

Breast cancer epidemiology

Cancer is a leading cause of death and an important barrier to increasing life expectancy in every country of the world^1,2. 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.

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).

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

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 EBC^7–11.

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

Assessment of breast cancer risk

Healthcare professionals may assess BC risk using these approaches^8,14,35:

• 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)³⁵.

Figure 6. Assessment in women at risk of breast cancer (Adapted³⁵).

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 are^3,4:

• expression of ER/PR, HER2 and proliferation markers, such as Ki-67
• gene expression assay
• 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 tumours^3,4.

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.

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 recurrence^6–8.

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 recurrence^3,7.

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.

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 disease^36,67,68. 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 use⁶⁹.

Progesterone receptor

In EBC, PR expression is associated with tumour grade, ER expression, Nottingham prognostic group and HER2- status⁷⁰. Evidence shows a better prognosis in PR+ cancers⁷⁰. The evaluation of PR expression does not appear to have a role in the ET choice in both locally advanced and mBC⁷¹.

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 found⁶⁹. 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 years⁷³. 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-off⁶⁹.

HER2

HER2+ is more frequently found in ER- tumours than in ER+ tumours. Only 12 % of ER+ BCs are positive for HER2 by amplification/overexpression of the gene⁷⁴.

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 protein⁶⁹.

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 settings⁶⁹.

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.

HER2-low

Almost half of the currently defined HER2-negative BCs show some degree of HER2 immunohistochemistry (IHC) expression and have been recently renamed as HER2-low BC⁷⁵. This is a recent designation defined as tumours with IHC staining of 1+, or 2+ without HER2 gene amplification⁷⁶. These tumours are targets for antibody–drug conjugates (ADCs), one of which, trastuzumab deruxtecan (T-DXd), was approved by the FDA in August 2022 and the EMA in January 2023 for treatment of metastatic BC in patients with HER2-low cancers who have received one or two chemotherapies or developed recurrent disease during or within 6 months of completing chemotherapy⁷⁷. This was based on results from the DESTINY-Breast04 clinical trial, where treatment with T-DXd resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy^77,78.

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 tumours⁶⁹.

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.

Figure 8. Early breast cancer treatment algorithm (Adapted⁴). 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 (Adapted³).

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 treatment¹³⁸. 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 ribociclib¹³⁸.

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)^{131,132,138-147}.

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