Introduction

Breast cancer is the most common cancer in women, but it can also develop in men, though this is less common. Breast cancer originates in the milk ducts or lobules of the breast and may spread to surrounding tissues or other organs if left untreated. However, early detection of breast cancer is usually not fatal and can often be effectively treated.¹ Early identification by self-examinations, mammograms, and clinical screenings dramatically improves survival rates. Recent advances in screening and therapies have reduced breast cancer deaths by more than 40%.¹

Risk factors for breast cancer

Breast cancer is the most common cancer among females, with approximately 1.7 million new cases each year. It is the fifth leading cause of cancer mortality, with about 0.5 million fatalities each year.

Estrogen levels play a key role in breast cancer development. Some reproductive factors, such as early menstruation, nulliparity, older age at first birth and late menopause, have been found to be risk factors for breast cancer due to prolonged exposure to estrogen.

Women with a first-degree relative diagnosed with breast cancer have approximately twice the likelihood of developing breast cancer themselves. While a small number of rare genetic variants with high or moderate penetrance, including mutations in BRCA1, BRCA2, TP53, PTEN, STK11, ATM, CHEK2, BRIP1, RAD51C, RAD51D, BARD1, and PALB2 genes, significantly increase breast cancer risk. Genome-wide association studies (GWAS) have also identified around 90 more common variants with low penetrance. Together, these genetic variants account for about 37% of the excess familial risk. Although some research has explored gene-environment interactions, stringent significance thresholds in GWAS present challenges in investigating such interactions thoroughly.

Breast cancer genetic variants and their interaction with reproductive factors have been given limited attention. Some genetic pathways were found to be associated with sexual hormone production or signalling. To the best of our knowledge, a systematic analysis of their interaction between these genetic variants in hormone-related pathways and reproductive factors influencing breast cancer risk has not yet been performed. The primary aim of this paper is to investigate the impact of the interaction between genetic variants in hormone-related pathways and reproductive factors on breast cancer risk.

Genetic and hereditary factors

• Family history: Having a family history of breast cancer puts one at greater risk
• BRCA1/BRCA2 mutations: Genetic mutations greatly increase the risk of getting breast cancer

Hormonal and reproductive factors

• Early menstruation/late menopause: Greater exposure to estrogen increases risk
• Hormone replacement therapy (HRT): Long-term use can enhance the risk for breast cancer

Lifestyle and environmental factors

• Smoking and alcohol: Both are associated with increased levels of risk
• Obesity and physical inactivity: Excess weight and a physically inactive lifestyle are risk factors
• Radiation exposure: Previous radiation therapy or occupational exposure increases the risk of developing cancer

Warning signs of breast cancer

Unusual nipple discharge, such as blood or clear fluid coming from a single breast without any stimulation, can be a warning sign of breast cancer. Other symptoms include:

• Lumps or thickening: Most typical sign; lumps can be painless, but should be checked out
• Changes in nipple shape/appearance: Retraction or inversion
• Skin changes: Redness, scaling, dimpling, or an orange-peel texture on the skin of the breast are warning signs
• Persistent pain: Unexplained breast pain requires medical evaluation²

Understanding nipple discharge

Nipple discharge (ND) can be an early indication of breast cancer. Intratumoral infiltrating carcinomas, which often do not present as a palpable mass, may manifest with pathological ND. Solitary ND, especially when it is not blood-stained, is often neglected by patients. Many women have limited awareness of breast cancer warning signs and the importance of breast self-examinations (BSE). Therefore, current efforts focus on raising breast cancer awareness and increasing knowledge about its warning signs for early detection.

We report two cases of breast cancer without a palpable mass, presenting with isolated ND that was whitish in color. In both cases, cytology of the discharge revealed highly pleomorphic cells, suggesting a high-grade malignancy. Mammography showed diffuse, extensive microcalcifications. A simple mastectomy with axillary clearance was performed in both cases. Histology revealed diffusely spreading intraductal carcinoma, with microinvasion present in one case. ND, if minimal or non-blood-stained, is usually overlooked by patients and sometimes by clinicians. 

ND presents a diagnostic challenge for clinicians. A range of diseases, including intraductal papillomas, mammary duct ectasia, breast cancer, pituitary adenomas, and breast abscess/infections, may present as ND. Both patients and doctors consider ND significant due to the potential association with underlying carcinoma. A thorough clinical examination is invaluable for establishing the pathophysiology, assessing the risk of malignancy, and planning appropriate treatment for patients presenting with nipple discharge. Imaging studies such as mammography, breast ultrasonography, and sometimes galactography can assist clinicians in making an accurate diagnosis and formulating a management plan. Depending on the underlying breast pathology, excision of a single or central lactiferous duct is often the preferred surgical intervention. When breast carcinoma is associated with ND, treatment typically involves either modified radical mastectomy or breast-conservation therapy, such as duct-lobular segmentectomy with adequate tumour-free margins (ideally greater than 1 cm), levels I and II axillary lymph node dissection, followed by breast irradiation.⁴

Normal vs. abnormal nipple discharge

Non-pathological nipple discharge is usually clear, milky, or white and may be caused by hormonal fluctuations, lactation, or stimulation. Non-pathological discharge—e.g., bloody or unilateral spontaneous discharge—can be a sign of underlying conditions, including cancer. 

Types of nipple discharge (clear, bloody, milky, etc.)

• Clear discharge: May be due to blocked ducts or cancer if unilateral
• Bloody discharge: Can be due to intraductal papilloma or breast cancer
• Milky discharge: Frequent during lactation or hormonal changes, such as menopause
• Green discharge: Usually associated with cysts or fibrocystic changes²

When to seek medical attention

Regular self-examinations enable individuals to detect changes in their breasts at an early stage. Any abnormal findings must be reported to a healthcare provider immediately.

Mammograms are essential in the early detection of breast cancer prior to the onset of symptoms. Women are typically recommended to start screening at age 40, although high-risk patients may require earlier and more frequent testing.

Prevention and risk reduction

Healthy lifestyle choices

A healthy weight, not smoking, avoiding too much alcohol, and regular physical activity can reduce breast cancer risk.

Regular medical check-ups

Routine tests like mammograms and clinical exams help detect cancer early.

Genetic counselling for high-risk individuals

Those with a history of breast cancer in their family or BRCA mutations may want to undergo genetic counselling to evaluate their risk and discuss preventive options such as increased screening regimens or prophylactic surgery.⁴

Summary

Breast cancer is the most common cancer in women and can present without a palpable lump, such as through nipple discharge (ND), which is often overlooked. Risk factors include genetic mutations (e.g., BRCA1/BRCA2), family history, prolonged estrogen exposure (early menstruation, late menopause, nulliparity), lifestyle choices (smoking, alcohol, obesity), and environmental exposure to radiation. ND, especially if bloody or unilateral, can be a warning sign of malignancy, even without a lump. Diagnostic tools include clinical exams, mammography, ultrasound, and cytology. Early detection through self-exams, regular screenings, and awareness of warning signs improves outcomes. Prevention includes maintaining a healthy lifestyle and seeking genetic counselling for high-risk individuals.