Breast Cancer Disease Background

Introduction

Breast cancer is the presence of a malignant breast nodule, mass, or abscess. 

Epidemiology

Breast cancer has the highest incidence among all cancers globally with as many as 2.3 million new cases in 2022. The highest incidence rates (>80 per 100,000 females) are observed in Australia, New Zealand, Western Europe, Northern America, and Northern Europe, while the lowest rates (<40 per 100,000 females) are observed in Central America, Eastern and Middle Africa, and South-Central Asia. It is the fifth leading cause of mortality globally, claiming 670, 000 lives just in 2022, with regions like Melanesia, Western Africa, Micronesia, Polynesia, and the Caribbean having the highest mortality rates. Global estimates also reveal striking inequities in breast cancer burden such that in countries with high Human Development Index (HDI), 1 in 12 women will be diagnosed with breast cancer in their lifetime and 1 in 71 women die of it. This contrasts with countries with low HDI where 1 in 27 women is diagnosed with breast cancer, while 1 in 48 women will die from it. The increased incidence rates seen in high HDI countries reflect the reproductive and hormonal risk factors (eg early menarche, later age at menopause, advanced age at first birth, less number of children of children, less breastfeeding, menopausal hormonal therapy, oral contraceptives), lifestyle risk factors (eg alcohol intake, excess body weight, physical inactivity), and increased detection. Breast cancer occurs in every country in the world in women at any age after puberty, but with increasing rates later in life. Breast cancer is still the most common cancer in women, occurring mostly in patients >50 years of age.  

In Asia, there were as many as 985,817 new cases of breast cancer in 2022 alone, claiming as many as 315,309 lives. Among the countries in Asia, the Philippines has the highest incidence of breast cancer with 1 in every 13 women being expected to develop the disease during their lifetime. Breast cancer is the most common cancer in the Philippines and is the leading cause of cancer death in females. In 2022, there were 33,079 new reported cases of breast cancer, with 20,953 deaths.

Pathophysiology

Breast cancer development is due to the malignant proliferation of epithelial cells lining the ducts or lobules of the breast. It is initially limited to a duct or lobule (in situ) without metastasis potential which may progress as time passes and spread in the breast tissue, lymph nodes, or other organs. 

Risk Factors

A previous history of breast cancer has an increased risk of developing new primary breast cancer. A history of invasive breast, lobular neoplasia (formerly called lobular carcinoma in situ [LCIS]), and ductal carcinoma in situ (DCIS) have the highest risk. Lifetime risk is at ≥20% based on a history of lobular carcinoma in situ or atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH).  

A previous history of epithelial ovarian or exocrine pancreatic cancer at any age; or prostate cancer at any age with metastatic, intraductal, or cribriform histology; those belonging to high- or very high-risk group; or with a family history of Ashkenazi Jewish ancestry, ≥1 close relative with breast cancer at ≤50 years of age or ovarian, pancreatic, metastatic, or intraductal or cribriform prostate cancer at any age, or ≥2 close relatives with breast or prostate cancer at any age.  

A confirmed biopsy of benign proliferative breast disease is also a risk factor for breast cancer development. A breast tissue biopsy showing proliferative disease with and without atypical cells has an elevated risk of developing breast cancer. Patients with benign breast disease that present with atypical hyperplasia carry the highest risk.  

A history of high-dose radiation exposure such as multiple exposures of therapeutic radiation to the chest for cancer at an early age (10-30 years old) increases the risk of breast cancer. Contralateral breast cancer has been shown to develop after high-dose radiation exposure. Patients with Hodgkin’s disease receiving radiotherapy at high doses are also at risk.  

For reproductive factors, nulliparity or first full-term pregnancy at the age of >30 years increases the risk for breast cancer development. Nevertheless, breastfeeding for >12 months is protective against breast cancer. Menarche at the age of <12 years and menopause at the age of >55 years are also known risk factors. Oral contraceptive use before the first full-term pregnancy, combination hormone replacement therapy, and long-term use of unopposed estrogen for >15 years by hysterectomized women have a mildly increased risk for breast cancer. The use of low-dose preparations poses a lower risk.  

Advanced age or woman ≥35 years has a 5-year risk of ≥1.7% for invasive breast cancer assessed using the modified Gail model. The Modified Gail model calculates the 5-year and lifetime probabilities of developing invasive breast cancer which can be used to identify women at increased risk by evaluating the risk of invasive breast cancer as a function of age, menarche, age at first live birth or nulliparity, number of first-degree relatives with breast cancer, number of benign breast biopsies, atypical hyperplasia in a previous breast biopsy, and race. Risk increases from 40 years old for premenopausal women and 50 years old for postmenopausal women.  


A family history of breast cancer should be known since there is an increased risk in women with breast cancer among young first-degree relatives. A sister has a higher risk than a mother. Carriers of BRCA1 and BRCA2 genetic mutations are also at high-risk. Women with these have an increased risk of developing other cancers like ovarian cancer. Other genes associated with genetic susceptibility to breast cancer include PTEN, TP53, CDH1, STK11, MLH1, MSH2, MSH6, and PMS2; genes currently being investigated include PALB2, CHEK2, ATM, RAD51C, RAD51D, and BRIP1.  

Other conditions with increased risk for breast cancer development include those individuals with characteristics for Li-Fraumeni syndrome (LFS) or Cowden syndrome or PTEN hamartoma tumor syndrome testing criteria, patients with higher breast density, and lifestyle factors such as body mass index of >25 (also associated with higher death rate) and lack of exercise. Alcohol consumption (eg beer) of >10 g/day especially in postmenopausal women has an increased risk for invasive breast cancer.  

Risk Factors for Disease Recurrence  

The risk for disease recurrence increases in patients with a palpable mass, larger mass size, higher grade tumors, close or involved margins, age of <50 years old, presence of lymphovascular space invasion, lymph node involvement, human epidermal growth factor receptor 2 (HER2) status of the cancer cells, and proliferative marker Ki67 index. 

Classification

Histologic Diagnosis  

Carcinoma in situ  

Carcinoma in situ is diagnosed when cancer cells are confined to the lobules or ducts without spreading into surrounding tissues in the breast or to other organs in the body. It includes lobular neoplasia or lobular carcinoma in situ and ductal carcinoma in situ.  

Invasive Breast Cancer  

Invasive breast cancer is the most common breast cancer where cancer cells infiltrate the interlobular stroma. It includes invasive ductal carcinoma, invasive lobular neoplasia, mixed tumors, medullary cancer, metaplastic tumors, inflammatory breast cancer, colloid carcinoma, tubular carcinoma, and papillary carcinoma. Colloid and tubular carcinoma are good prognosis cell types which are usually HER2 negative.