BREAST DISEASES

2.1.1 Subtypes and prevalence of benign breast lesion

Breast diseases are categorized into benign and malignant tumors. Benign breast lesions are derived from different breast components (epithelial, stromal, adipocyteal, or vascular) ¹. Benign breast lesions are common. The actual incidence of benign breast conditions remains undetermined. The majority of symptomatic patients have benign tumors ²; approximately 75 % of breast lesions biopsied are benign ³. Nonetheless, it has been proposed that only 10-20 % of all benign breast conditions are verified histopathologically ^1,4.

The fibrocystic changes occurring in the breast are of interest, because they are the most frequently biopsy-confirmed benign breast conditions ². Three subgroups of fibrocystic changes have been identified; non-proliferative lesions, proliferative lesions without atypia, and lesions with atypical hyperplasia ^1,2. Lesions with a proliferative tendency, especially atypical hyperplasia, have an increased relative risk for breast cancer development ^5,6. In a large study sample of over 10 000 breast biopsies, 69 % of samples represented non-proliferative changes and only 3.6 % were atypical hyperplasia ⁷. A review of post-mortem studies indicated that nearly every other woman may develop a fibrocystic breast change ^1,4.

2.1.2 Malignant breast diseases 2.1.2.1 Breast cancer subtypes

Malignant breast tumors are categorized as either non-invasive (in situ) or invasive carcinomas ^8,9. Approximately 20 % of breast carcinomas are non-invasive ¹⁰. Non-invasive and Non-invasive carcinomas are divided into several subtypes based on their histopathology ¹¹. The share of these subtypes according to the National Cancer Institute’s Survey, Epidemiology, and End Results Program is presented in Table 1.

2.1.2.2 Incidence, survival and mortality rates

Breast cancer is the most common cancer in women (1.67 million new cancers worldwide in 2012) and accounts for 25 % of all female cancers ¹³. The incidence of breast cancer varies by region, with the highest rates reported in Western Europe and the United States with the lowest rates in Africa and Asia ¹⁴. The global incidence of breast cancer is increasing ¹⁵.

Five-year survival rates of breast cancer vary regionally and are 89.7 %, 81.8 % and 90.6 % for the United States, the European Union and Finland, respectively ^11,16,17. In the developed regions, breast cancer is the the most frequent cause of cancer deaths among women ¹⁸, even though the mortality has declined due to the implementation of screening and adjuvant therapies ^19–21. Estimated breast cancer incidence and mortality rates per 100 000 women at a global level, in the United States, the European Union and Finland are presented in Table 2.

CIS = carcinoma in situ. ¹ Lobular CIS is considered a benign tumor in the American Joint Committee for Cancer (AJCC) staging. Other cancer types occurring in breasts, i.e. sarcomas, phyllodes tumors and breast lymphomas, are not staged as breast cancers in UICC or AJCC staging manuals. ^8,9,12

Table 1. The percentage share of invasive and non-invasive breast cancer subtypes according to their histology in 2010-2014 in the United States ¹¹.

Invasive Non-Invasive

Cancer subtype Share (%) Cancer subtype Share (%)

Ductal carcinoma 73.5 Ductal CIS 85.0

Lobular carcinoma 9.3 Lobular CIS¹ 11.6

Mixed ductal and

lobular carcinoma 9.1 Mixed ductal and

lobular CIS 2.7

Mucinous carcinoma 1.9 Other CIS 0.7

Papillary carcinoma 0.6 Tubular carcinoma 0.5

Other 5.1

Table 2. Estimated age-standardized incidence and mortality rates of breast cancer in 2012 ¹³.

Incidence (per 100 000 females) /

Total number Mortality (per 100 000 females) / Total number

World 43.1 / 1 700 000 12.9 / 520 000

The United States 92.9 / 230 000 14.9 / 44 000

The European Union 80.3 / 360 000 15.5 / 92 000

Finland 89.4 / 4500¹ 13.6 / 860

1 According to the Finnish Cancer Registry, there were 5161 female breast cancers diagnosed in 2015 ¹⁷.

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2.1.3 Female breast cancer risk factors

There are non-modifiable and modifiable lifestyle-related risks factors for breast cancer ²². Non-modifiable factors are characteristics that predispose a person to an increased risk of breast cancer and cannot be altered ²². Lifestyle-related factors are less significant for breast cancer development than non-modifiable risk factors ¹⁰.

2.1.3.1 Non-modifiable breast cancer risk factors

Breast cancer is a hundred times more likely to affect women than men ^14,18. The risk of being diagnosed with a breast cancer increases with age ²³. Having a personal history of a non-invasive or an early invasive breast cancer or a high risk lesion predisposes a woman to breast cancer ^6,10. A history of other cancers (endometrium, ovary and colon) has been associated with an increased breast cancer risk ²⁴.

A family history of breast and / or ovarian cancers increases an individual’s risk of breast cancer; the number of first-degree relatives and the age of the affected relative(s) at the time of breast cancer diagnosis also plays a role ^10,25. It has been estimated that 10-30 % of breast cancer cases are attributed to hereditary factors, but only 5-10 % of breast cancer cases have a strong inherited background ²⁶. Women with a rare high-prevalence genetic predisposition are more likely to be diagnosed with breast cancer. It has been estimated that 35-65 % of women having mutations in BRCA1, BRCA2 or PALB2 cancer susceptibility genes will develop a breast cancer by the age of 70 years ^24,27–30.

Higher mammographic breast tissue density, i.e. the relative amount of breast’s glandular and connective tissues to the portion of fatty tissue, has been shown to increase the risk of breast cancer. An increased mammographic breast density is an established risk factor for the development of female breast cancer, only less significant than the risks posed by the patient’s age, existing breast cancer and BRCA mutations ^31,32. Other known risk factors include high systemic estrogen levels, early menarche and late menopause ³³.

2.1.3.2 Lifestyle-related breast cancer risk factors

The higher breast cancer incidence in high-income countries is partly attributable to a higher prevalence of lifestyle-related breast cancer risk factors ³⁴. Lifestyle-related risk factors include adult weight gain, excess body weight, use of menopausal hormone therapy or oral contraceptives, physical inactivity, alcohol consumption, high-dose radiation to breast and reproductive and hormonal factors ²⁴.

2.1.4 Breast cancer prognosis

Clinical and biological prognostic factors provide information on the overall cancer outcome in untreated individuals ^35,36. Tumor size, axillary nodal status and the presence of metastasis are well-defined anatomical prognostic factors. It has been

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proposed that biological prognostic factors should also be incorporated into risk models in order to obtain a more refined assessment of prognosis ^8,12,37. Tumor histology, nuclear grade, estrogen / progesterone receptor (ER / PR) statuses, human epidermal growth factor 2 (HER2) overexpression / amplification, vascular invasion and the expression of proliferation markers (e.g. Ki-67) are the most often used prognostic factors in clinical practice for prognosis estimation and treatment tailoring

38–40. In addition, during the past few years, gene expression panels have been

introduced into clinical practise to aid in prognosis determination 12,38,41,42.

2.1.4.1 Anatomical staging of breast cancer

The TNM classification system is the most widely used system for staging breast cancer. Staging of invasive breast cancers using a four-level system (stages I-IV) is based on the largest diameter of the primary tumor (T), regional lymph node involvement (N) and distant metastasis (M); non-invasive (in situ) breast cancers are referred to as Tis ^8,9,43. A larger tumor size and an increased number of involved lymph nodes have been associated with decreased breast cancer survival ⁴⁴. The spread of cancer cells from the primary tumor to distant organs, i.e. distant metastasis (stage IV disease), is a determinant of poor prognosis and a contributor to disease related mortality ^45–47. The relative 5-year survival rates in the US between the years 2007 and 2013 were 100.0 %, 92.0 %, 73.2 % and 26.5 % for stages I to IV, respectively

48.

2.1.4.2 Prognostic biological factors in early breast cancer

Histopathological analysis and grading are routinely performed. Grading is performed using the Nottingham Grading System (NGS) ⁴⁹ that relies on the evaluation of the degree of tubule or gland formation, nuclear pleomorphism and mitotic count ⁵⁰. Well-differentiated low-grade tumors have a better prognosis than poorly differentiated high-grade tumors ⁴⁹. Immunohistochemistry has been used to determine the expression of intracellular estrogen and progesterone receptors; 70 % of invasive cancers are ER positive and 50 % are PR positive ⁵¹. ER positivity has been correlated to prolonged disease-free survival ^51,52; the role of PR as an independent factor remains unclear ^53,54. Overexpression / over-amplification of the transmembrane receptor HER2 detected either by immunohistochemistry or in situ hybridization is present in 15 to 30 % of invasive breast carcinomas ^38,55,56, and it has been associated with higher mortality, greater recurrence rates and more aggressive diseases ⁵⁷. Nonetheless, in the era of HER2-targeted therapies, patients with HER2 positive breast cancers have similar 5-year overall and relapse free survival rates as patients with HER2 negative, hormone receptor positive diseases ⁵⁸. Increases in the levels of a proliferation marker (e.g. nuclear protein Ki-67) expression have been associated with poorer overall disease-free survival ^59,60.

Tumors may be grouped into intrinsic subtypes according to their biological prognostic factors to allow a more detailed prognostic assessment (Table 3). The

luminal A subtype is associated with a highly favorable prognosis; the luminal B subtype has a worse prognosis in comparison to the luminal A subtype ⁶¹. The introduction of the HER2-targeted therapies has markedly improved the survival of patients with HER2 positive tumors while the triple negative tumors have an unfavourable prognosis in comparison to other tumor subtypes ⁶¹.

Recently, gene expression panels have been introduced to complement the pathological assessment in the prognostic evaluation 12,38,41,42. Genomic tests, MammaPrint, Oncotype DX, EndoPredict, Breast Cancer Index and Prosigna Breast Cancer Prognostic Gene Signature Assay with varying eligibility criteria have been validated and / or are under evaluation for the estimation of the breast cancer recurrence risk ⁶². These genomic tests may help in determining breast cancer recurrence and the benefit of adjuvant treatments ^63,64.