Early-Stage Metastatic Breast Cancer

Introduction

As per the global data collected by the World Health Organization data, breast cancer represents the most familiar malignant neoplasm in female patients. It impacts around 2.1 million women yearly.1 Breast cancer is a disease that is associated with a wide range of clinical behaviours and varied biological features. The incidence of early-onset breast cancer (EOBC) has been estimated to be around 6%–10% of all breast cancer cases in developed countries. However, in developing countries, the incidence is around 20%.2

Breast cancer, mainly cultivates in the breast tubes, lobules or connective tissue. Even though different criteria and classifications are present in literature, the most characteristic types of breast cancer based on molecular subtypes are luminal A, luminal B, human epidermal growth factor receptor 2 (Her2) positive and lastly, triple negative breast cancer (TNBC). All these types have distinctive features in terms of metastases, prognosis, and treatment methods used.3 Estrogen receptor (ER) positive tumors, also known as luminal (LUM) subtypes account for around 70% of breast cancer cases. These tumors characteristically express increased levels of estrogen and progesterone receptors.4 The HER2 subtype represents about 10–15% of all breast cancer cases. It is under the control of the receptor tyrosine kinase (RTK) oncogene ERBB2. These tumors are associated with overexpression of the ERBB2 gene. This tyrosine receptor kinase (Her2) has been used in a reasonably effective manner for treating Her2-positive breast cancer.5,6. TNBC is the most difficult form of breast cancer to manage as it does not express any estrogen receptor (ER), progesterone receptor (PR), and Her2. Even though it accounts for only around 15–20% of breast cancers, it is typically diagnosed at a late stage which associates it with an increased recurrence rate and decreased survival rate.7

Furthermore, each cancer subtype is defined by the stage at which it is diagnosed. Depending on the stage of cancer, the treatment and the further management of the patient are planned by the concerned team of doctors. Stages of breast cancer usually depend upon the tumor size and type and how much has the tumor cells penetrated the breast tissues.8 Whereas stage 0 represents the non-invasive tumor and stage 4 is associated with the invasive tumor.

Metastatic breast cancer (Stage 4)                                                                                   

Breast cancer is often deemed as a systemic disease because an increased percentage of patients (>50%) develop metastatic disease. Metastatic breast cancer is the last stage of breast cancer when the tumor has metastasized to different organs like lungs, liver, bone etc. This not only exaggerates the symptoms but also greatly affects the quality of life of the patients. To understand and treat this stage, scientists are investigating the factors and conditions that cause the cancer cells to metastasize i.e. move to other body organs. So, now the question that comes to mind is:

How does cancer spread (metastasize)?

Metastasis is a very complex and regulated process through which a primary tumor develops into a distal secondary tumor. It is a characteristic feature of cancer and it leads to treatment failure and even the death of many patients. It involves various cellular mechanisms like separation from the primary tumor, invasion, elusion from immune surveillance, and finally managing the tissue microenvironment. Specifically, epithelial–mesenchymal transition (EMT) is necessary for metastasis in most cancers.9 EMT is a process in which epithelial cell polarity and intercellular cohesion are lost. It is very important for the start of metastasis in breast cancer.10 The different pleiotropic transcription factors like TWIST, SNAIL, and zinc finger E-box-binding (ZEB) are essential molecules in the regulation of EMT. Additionally, cell surface proteins play an essential part in breast cancer metastasis. Metastasis is initiated by the interactions between cancer cells and the cell surface. This facilitates cell adhesion and hence invasion.11 Furthermore, other factors that contribute towards metastasis in breast cancer are immune cells and the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) also play varied roles in various micro-environmental signalling. Advanced studies have shown that cells which have stem cell characteristics i.e. they can self-renew and differentiate into other cell types play an important part in the process of tumor initiation, its progression, and finally metastasis.12,13

In simple words, a set of factors like transcription factors, cytokines, cell surface proteins, tumor microenvironment all play an essential role in metastasis. By the interaction among these factors and activation of various molecular pathways, the cancer cells acquire the ability to migrate into different organs through the bloodstream or lymphatic vessels which leads to malignancy.

Symptoms of metastatic breast cancer

In the metastatic setting various symptoms are present. It is usually based on the site of metastasis. However, the most common symptoms are pain, depression, fatigue and insomni. In one study, the mean number of symptoms observed in 56 metastatic breast cancer patients was 14. Decreased sexual function was the most commonly reported symptom, worry was the most critical symptom and the pain was the most disturbing symptom.15

Bone metastasis: Bone is the most common site for metastases in breast cancer. A substantial number of patients suffer from skeletal related problems due to bone metastasis. Some of these are spinal cord compression, pathological fractures, bone marrow infiltration, hypercalcemia, and severe bone pain. All these problems characteristically decrease the quality of life in patients.16

Brain metastasis: Breast cancer brain metastasis (BCBM) occurs in approximately 10–30% of patients with metastatic breast cancer. It worsens both the sensory and cognitive functions of patients.17 The common symptoms associated with it are dizziness, nausea, vomiting, severe headache, hemiparesis, visual changes and seizures.18

Liver metastasis: In comparison with lung and bone metastases, liver metastases patients are associated with a poorer outcome. Their median survival range is around 14–16 months, no matter which treatment is provided to the patient.19 On presentation, this breast cancer liver metastasis (BCLM) has been observed to cause nausea, abdominal discomfort, and anorexia, along with symptoms and physical signs indicative of cachexia such as jaundice, painful hepatomegaly and ascites.20

Lungs metastasis: It is commonly diagnosed in TNBC with incidence reaching up to 40% in these patients.21 Furthermore, the clinical presentations and consequences associated with lung metastasis are exceptionally critical. Cough, pain, pleural effusion, hemoptysis, and pulmonary dysfunction are the most common clinical symptoms which greatly affect the quality of life and survival of patients.22

How is metastatic breast cancer diagnosed?

The clinical history of patients is of utmost importance in diagnosing breast cancer. It must comprise facts like menopausal condition, age at menarche, earlier pregnancies and use of any kind of hormone replacement therapy after menopause or of oral contraceptives. Personal history should be examined to learn about the age at diagnosis of breast cancer, any previous breast biopsies and any radiological treatment for other cancer. It should also be taken into consideration if any first degree relative has breast or ovarian cancer. Patients should also be examined for breast pain, pain in the bone, weight loss, tiredness and any kind of discharge from nipples.23 The breast, along with the area around the neck, collarbone and armpits should be examined.24 Breasts should also be observed for any deformities such as lumps.

Mammography: It is considered the gold standard test for early detection of breast cancer.25 It helps to identify lumps in dense tissue.

Ultrasound breast imaging: Ultrasound of the entire breast helps to get a detailed presentation of breast tumors that are generally not measured by mammography, mainly in thick breasts where mammography is less sensitive.26 This imaging helps to know about the size and position of a tumor whether it is solid or filled with fluid.

Nuclear medicine: CT and PET alone or in combination helps in enhancing recognition and vicinity of disease.

Tumor markers: Various tumor markers like CA15-3, and 27.29 are measured to detect breast cancer.

Estrogen and progesterone receptors: The presence of estrogen and progesterone receptors including HER2 antigen in breast cancer tissues obtained after biopsy using immunohistochemistry is widely used to confirm the diagnosis. These tests provide information about the aggressiveness of cancer and its response to certain drugs that are being used for the treatment of breast cancer.

MRI further provides more precise results and is really important to women who develop breast cancer due to the genetic mutation in BRCA1 and BRAC2 which are present along with the axillary lymphadenopathy.

Treatment

With advancements in scientific technology, a range of treatments are available for breast cancer. However, the main aim is to comfort the patient and improve their quality of life. Effective communication between patients and doctors plays an essential role to enhance the clinical outcome. Breast cancer treatment strategies vary depending on the stage of cancer—its place, volume and also whether it has progressed to other organs of the body and also the physical condition of the individual. Present treatment methods for breast cancer are targeted therapies, radiation therapy, hormonal treatment and surgery.27

Prevention of metastatic breast cancer

Primary prevention mainly includes the process of removing the causes that lead to disease occurrence and enhancing the immune system in the population. World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) have observed a strong impact of diet and physical activity on cancer development. According to their recommendations, a healthy diet in cancer prevention is rich in vegetables, fruit, legumes and cereals. It consists of less quantity of red meat and salt.28 Furthermore, increased physical activity and decreased alcohol consumption are some factors that help in the prevention of cancer development.

Secondary prevention aims to terminate the development of the disease before its full symptoms are diagnosed. This may help in impeding or preventing the development of a malignant tumor. Screening for breast cancer by mammography or ultrasound is the best example of such a prevention. Regular health checkups are of utmost importance in the early diagnosis of the disease and hence its prevention. Moreover, knowledge about the disease is equally important.29

Hence, to control disease morbidity, early diagnosis is the key. Therefore, extending the knowledge of the people regarding the impact of breast cancer development and further educating them about the prevention and treatment possibilities to gain control over this disease by implementing modifications of their habits is an essential aspect.

Prognosis

Even though the morbidity of the disease is quite high, patients with breast cancer show better prognoses as compared to other cancers. According to the American Cancer Society’s two yearly updates on female breast cancer, the 5 and 10 year survival rate is 91% and 84% respectively.30 However, this survival rate decreases significantly if the patients develop metastases. 99% is the overall 5-year relative survival rate for localized diseases and for regional diseases it is 86%, this drops to around 27% for diseases with metastasis.31 Despite technological development and advancement in medical science, these patients generally have a poor prognosis (median survival time of just 2–3 years).32 A large number of breast cancer patients diagnosed at an early stage of the disease are suitable for surgical resections and adjuvant systemic therapies. This leads to longer survival.33

Lifestyle modifications

As discussed above in primary prevention, lifestyle modifications not only prevent the recurrence of breast cancer but also help in improving the quality of life. It gives the patient a feeling of wellness. Studies are being performed to understand the connection between the lifestyle and occurrence of cancer. The presence of obesity in breast cancer varies across menopausal status and disease subtypes. In one of the studies, it has been observed that increased BMI is associated with a decreased risk of premenopausal breast cancer, but strongly associated with high risk after menopause.34

Breast cancer cells have high expression of leptin receptors. Leptin is basically a hormone secreted by fat cells (adipocytes). Hence, breast cells are highly susceptible to high leptin levels present seen in obese patients.35 It seems likely that the marked increase in the occurrence of breast cancer is related to the high intake of dietary calories and a decrease in physical exercise over the past century and largely due to the pandemic situation in the past 2 years. Hence, with little lifestyle modification, the patients can give themselves a better quality of life. However, individualized programs for the patients should be planned with the concerned oncologist's team, professional dieticians and fitness experts.

Summary

Regardless of recent advances in medical technology, metastasis still remains the leading cause of death in breast cancer patients. Even though intensive research has been done to understand the mechanisms leading to breast cancer metastasis, a lot still needs to be done to develop drugs that totally inhibit these mechanisms of metastasis. Additionally, due to a sedentary lifestyle, increased intake of fast foods, and low dietary fibre consumption the incidence of breast cancer has increased. Hence, to prevent the occurrence or recurrence of breast cancer, it is important that a team of oncologists, dieticians and fitness professionals should work together to make customized treatment regimens for the patients. Also, the management should not involve the treatment of the patient but also improve their quality of life by giving them proper education. 

References

  1. Breast cancer [Internet]. . Available from: https://www.who.int/news-room/fact-sheets/detail/breast-cancer
  2. Gómez-Flores-Ramos L, Álvarez-Gómez RM, Villarreal-Garza C, Wegman-Ostrosky T, Mohar A. Breast cancer genetics in young women: What do we know? Mutat Res Rev Mutat Res. 2017 Oct;774:33–45.
  3. Jin X, Mu P. Targeting Breast Cancer Metastasis. Breast Cancer Basic Clin Res. 2015;9(Suppl 1):23–34.
  4. Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC. Past, present, and future challenges in breast cancer treatment. J Clin Oncol Off J Am Soc Clin Oncol. 2014 Jul 1;32(19):1979–86.
  5. Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest. 2011 Oct;121(10):3797–803.
  6. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011 Nov 29;9(1):16–32.
  7. Garrido-Castro AC, Lin NU, Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019;9(2):176–98.
  8. Heim E, Valach L, Schaffner L. Coping and psychosocial adaptation: longitudinal effects over time and stages in breast cancer. Psychosom Med. 1997 Aug;59(4):408–18.
  9. Park M, Kim D, Ko S, Kim A, Mo K, Yoon H. Breast Cancer Metastasis: Mechanisms and Therapeutic Implications. Int J Mol Sci. 2022 Jun 18;23(12). 
  10. Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34.
  11. Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 2004 Apr;5(4):365–74.
  12. Song K, Farzaneh M. Signaling pathways governing breast cancer stem cells behavior. Stem Cell Res Ther. 2021 16;12(1):245.
  13. Su C, Zhang J, Yarden Y, Fu L. The key roles of cancer stem cell-derived extracellular vesicles. Signal Transduct Target Ther. 2021 08;6(1):109.
  14. Irvin W, Muss HB, Mayer DK. Symptom Management in Metastatic Breast Cancer. The Oncologist. 2011 Sep 1;16(9):1203–14.
  15. Sarenmalm EK, Öhlén J, Jonsson T, Gaston-Johansson F. Coping with Recurrent Breast Cancer: Predictors of Distressing Symptoms and Health-Related Quality of Life. J Pain Symptom Manage. 2007 Jul 1;34(1):24–39.
  16. Filippiadis D, Mavrogenis AF, Mazioti A, Palialexis K, Megaloikonomos PD, Papagelopoulos PJ, et al. Metastatic bone disease from breast cancer: a review of minimally invasive techniques for diagnosis and treatment. Eur J Orthop Surg Traumatol. 2017 Aug 1;27(6):729–36.
  17. Wang Y, Ye F, Liang Y, Yang Q. Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies. Br J Cancer. 2021 Oct 12;125(8):1056–67.
  18. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis in breast cancer: a comprehensive literature review. J Neurooncol. 2016 May 1;127(3):407–14.
  19. Ruiz A, Hillegersberg R van, Siesling S, Castro-Benitez C, Sebagh M, Wicherts DA, et al. Surgical resection versus systemic therapy for breast cancer liver metastases: Results of a European case matched comparison. Eur J Cancer. 2018 May 1;95:1–10.
  20. Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, et al. Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis. 2015 Feb 1;32(2):125–33.
  21. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010 Nov 11;363(20):1938-48. 
  22. Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol Ther. 2018 Apr 30;19(10):858–68.
  23. Shah R, Rosso K, Nathanson SD. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol. 2014 Aug 10;5(3):283–98.
  24. Kolb TM, Lichy J, Newhouse JH. Comparison of the Performance of Screening Mammography, Physical Examination, and Breast US and Evaluation of Factors that Influence Them: An Analysis of 27,825 Patient Evaluations. Radiology. 2002 Oct 1;225(1):165–75.
  25. Sardanelli F, Giuseppetti GM, Panizza P, Bazzocchi M, Fausto A, Simonetti G, et al. Sensitivity of MRI Versus Mammography for Detecting Foci of Multifocal, Multicentric Breast Cancer in Fatty and Dense Breasts Using the Whole-Breast Pathologic Examination as a Gold Standard. Am J Roentgenol. 2004 Oct 1;183(4):1149–57.
  26. Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20(3):734–42.
  27. Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017 Dec;50(1):1–23.
  28. Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr. 2020 Apr;150(4):663–71.
  29. Kolak A, Kamińska M, Sygit K, Budny A, Surdyka D, Kukiełka-Budny B, et al. Primary and secondary prevention of breast cancer. Ann Agric Environ Med. 2017 Dec 23;24(4):549–53.
  30. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019 Nov 1;69(6):438–51.
  31. Noone AMHN, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, et al editors. SEER Cancer statistics review, 1975–2015: National Cancer Institute; 2018
  32. Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the Number of Women Living with Metastatic Breast Cancer in the United States. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2017 Jun;26(6):809–15.
  33. Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer. 2019 Nov 12;19. 
  34. Kerr J, Anderson C, Lippman SM. Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 2017 Aug 1;18(8):e457–71.
  35. Ishikawa M, Kitayama J, Nagawa H. Enhanced Expression of Leptin and Leptin Receptor (OB-R) in Human Breast Cancer. Clin Cancer Res. 2004 Jul 1;10(13):4325–31. 
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Dr. Aastha Malik Dahra

Doctor of Philosophy - PhD, Life Sciences (Diabetes and Gene Polymorphisms), Post Graduate Institute of Medical Education and Research, Chandigarh

"I was chosen for the PhD program through a Senior Research Fellowship awarded by the Indian Council of Medical Research, New Delhi, India.

My thesis work focused on the association of genetic polymorphisms in Angiotensin converting enzyme (ACE), Serotonin transporter (SERT), Adrenergic receptor beta 2 and Adrenergic receptor beta 3 with gastrointestinal dysmotility in Type 2 Diabetes Mellitus patients. "

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