The first known case of breast cancer was recorded in an ancient Egyptian text 'Edwin Smith Papyrus' that dated back to 1600 BC. To date, it is the second leading cause of cancer death in women. In recent years, the incidence rates have continuously increased, but the death rates have decreased primarily due to early screening and better treatment regimes. We need a better understanding of the molecular profile of cancer to develop strategies for combating this disease.
Cancer alters both the morphological and biochemical properties of multiple cell types in a tissue. The biochemical alterations in different components of the tissue are responsible for tumor development and its subsequent progression. Breast cancer can be described as a series of molecular and cellular changes leading to breast alterations, typically a lump or a lesion. One of the significant challenges for its management is the molecular heterogeneity of the tumor. Currently, it is categorized into four major subgroups, i.e., a) hormone positive and slow-growing; b) hormone positive and fast-growing; c) hormone receptors negative and HER2 (human epidermal growth factor receptor 2) positive; d) triple-negative breast cancer (TNBC), that determine the risk factors, treatment, and potential organ sites of metastasis (spread of cancer to other organs of the body).
Additionally, grade and the tumor stage are often used to decide further the course of action/treatment within these subtypes. Tumor grade is determined based on the appearance of the cells under the microscope. It ranges from grades 1 – 3, with higher grades representing faster-growing tumors. The tumor stage is a function of the tumor's size and its extent of spread in the body. It is important to determine the management and treatment regimens for the patient. Stage 0 tumor, where the cells are confined to a milk duct and have not yet grown to the rest of the breast tissue, is referred to as ductal carcinoma in situ, and other stages (1-4) are termed as invasive breast cancer. Advanced stage tumors (stage IV) are referred to as metastatic breast cancer that has spread to other organs, mainly the liver, brain, bone, and lungs. The 5-year survival rates drop drastically from 99% in stage 0 tumors to 27% in stage IV cases, making early detection imperative for improved patient care and disease management.
What can we do to save lives?
The first step to decreasing our society's cancer burden is to adopt a healthy lifestyle at an individual level and as an ecosystem. Even though predominantly genetic factors cause breast cancer, lifestyle changes can significantly reduce the risk. Maintaining a healthy weight by eating a balanced diet, regular physical activity, not smoking, and limiting alcohol consumption is crucial for decreasing breast cancer risk.
The next key to survival and better patient outcomes in breast cancer is early detection. There are many indicators that we can keep track of as an individual at home. It is crucial to keep in mind that just the presence of these symptoms doesn't always correlate to breast cancer. Most alterations manifest around the nipple area, like changes in how it looks, feels, and any fluid discharge. Any nipple tenderness or lump in the surrounding regions warrants further investigation by an experienced clinician. The National Breast Cancer Foundation lists some other unusual changes in the breast's shape and size, particularly evident on one side, inverted nipple, or alterations in the breast's skin as early indicators of the disease. To proactively track these changes, all women should perform breast self-examination at least once a month. A step by step guideline to perform these evaluations is detailed here.
Additionally, women should undergo a clinical breast exam once a year, where a clinician can examine some of the possible abnormalities or warning signs. This can help in determining preventive care steps if needed. If any suspicious areas are found during self-examination or a clinical exam, they are further investigated by a mammogram (x-ray imaging) and a biopsy.
What is happening at the systemic level: Screening and Diagnosis?
Suspicious areas or lumps are composed of fatty cells, cancer cells, or simple cysts. Combining imaging techniques such as mammography, ultrasound, and MRI helps decipher these unusual changes. Mammography helps identify non-palpable mass and any subtle changes in the breast tissue. Ultrasound is carried out when a mass is already recognized by self/clinical examination, and nature (cystic or solid) has yet to be determined. It is especially important in younger women with dense breasts where mammography can give confounding results. Clinical trials are currently ongoing to see if 3D mammography (digital breast tomosynthesis) can better and advance breast cancer screening. Magnetic resonance imaging (MRI) can help capture lesions hidden in dense tissue and is especially recommended for women younger than 40 years with an elevated risk for breast cancer (family history of breast cancer/ hereditary genetic mutations). The American Cancer Society lists the screening recommendations for the management of high-risk groups here. After these screening procedures, a biopsy is taken to test and diagnose the breast lesion if a solid mass is detected. The biopsy is stained for different molecular markers and visualized under a microscope by trained pathologists to identify the type of cells and report the final diagnosis. Conventionally, diagnosis is based on the structural (morphological) differences in the cellular, nuclear architecture, and growth patterns. Various molecular markers are used in clinics to capture the tumor's molecular characteristics to estimate the course of the disease progression. Finally, tumor grading and staging are done in the pathology report to determine different treatment strategies.
What is happening at the systemic level: Treatment?
Many women with early-stage breast cancer can either opt for breast-conserving surgery (parts of affected tissue from the breast is removed) or mastectomy (entire breast is removed). Often surgery is accompanied by radiation or chemotherapy. Chemotherapy and radiation are administered to kill any leftover cells not captured in imaging tests and lower cancer risk coming back. In some cases where the tumor is too big, chemotherapy and radiation are given before the surgery (neoadjuvant). For hormone (HR) positive and human epidermal growth factors (HER2) positive breast cancer types, targeted therapy to blocking tumor growth is given in addition to the surgery. This therapy, also known as endocrine therapy, has fewer side effects than chemotherapy and improves survival rates. With the introduction of these targeted approaches in the last 15 years, the overall survival rates of advanced-stage patients have improved from about 1.5 years to 5 years. Triple-negative breast cancer (TNBC), i.e., HR- and HER2, is relatively more aggressive and challenging to manage. This category has the least treatment options apart from traditional chemotherapy, and research advances in this area are needed. The treatment options for the different stages of breast cancer can also be categorized as listed below-
Stage 0 breast cancer
Breast-conserving surgery (BCS) or mastectomy (surgery to remove entire breast tissue), hormone-positive cases are given tamoxifen targeted therapy to lower the recurrence risk.
Stage 1 and 2 breast cancer
BCS (+ radiation therapy) or mastectomy, nearby lymph nodes are checked for any additional tumor spread. Hormone positive patients are given targeted therapy, sometimes in combination with chemotherapy. For HER2+ tumors, HER2 targeted therapies like trastuzumab (monoclonal antibody) are also provided.
Stage 3 and 4 breast cancer
Neoadjuvant chemotherapy (therapy given before surgery), Herceptin for HER2+ tumors is given to shrink the tumor followed by BCS or mastectomy, lymph nodes biopsies to remove the cells spread to the lymph nodes. Most cases also require radiation, in addition to the targeted therapies. For triple-negative breast cancers (TNBC), chemotherapy is majorly used. Recent advances in immunotherapy discussed in the next section have offered new treatment options for this subgroup of patients.
Where is research taking us?
In the last decade, there have been significant advances in diagnostic and treatment regimens for breast cancer management. Due to the issues of variability and turnaround times in manually assessing slides on a microscope, many efforts have been undertaken to digitize patient slides and develop digital methods to characterize cancer. Many studies have reported a significant increase in diagnostic accuracies by coupling artificial intelligence (AI) based methods with human interpretation. Additionally, the genomic revolution has also enabled critical advances in personalized cancer care. This has opened new avenues for capturing tumor heterogeneity and enabling personalized treatment. Many commercially available molecular assays such as OncotypeDX, Prosigna, MammaPrint, EndoPredict, etc. provide additional information about disease progression compared to conventional immunohistochemical markers. These assays guide clinicians to take precise and individualized treatment decisions, thereby avoiding the overtreatment of patients. This is especially critical because radiation/chemotherapy leads to many side effects, and mastectomy can have a significant psychological impact. The emergence of resistance to existing targeted therapies and lack of options for TNBC had led to the development of immunotherapy-based approaches. Our immune system has checkpoints to initiate the immune response of our body. Cancer cells sometimes interact with these checkpoints to block the immune cells from attacking them. Immunotherapy drugs are used to restore the immune system to slow the growth of tumor cells. Recently many clinical trials have been executed to study the impact of combination therapies (targeted hormone therapy + immunotherapy) on improved patient survival rates. Emerging technologies to investigate breast cancer at the spatiotemporal level by coupling clinical imaging with genomics and data science approaches will open new avenues for comprehensive patient evaluation and optimized, personalized therapy for women worldwide.
I thank Rohil Jain and Mayank Garg for their useful comments and feedback.