By - October 17, 2022
One in eight women in the United States (U.S.) will develop invasive breast cancer (BC) over the course of their lifetime.1 Although this diagnosis is undoubtedly life-altering, due to advances in scientific knowledge, it is no longer a death sentence. Albeit no accurate statistics are available, from the 1920s to the present, the five-year survival of patients with breast cancer has improved from less than 5% to 90% in the U.S.2
Building upon earlier work in surgery and the discovery of the radioactive element radium by Marie and Pierre Curie, the revolution in breast cancer diagnosis and treatment started during the first few decades of the twentieth century. It was in 1896 when X-rays were used for the first time by Emil Grubbe to irradiate a female patient suffering from locally advanced breast cancer.3 In 1913, German surgeon Albert Salomon used X-rays to study 3,000 mastectomies and correlate radiographic, gross, and histological findings.4 During that time, the standard treatment for BC patients was radical mastectomy. Introduced in the 1880s by William Halsted, radical mastectomy entailed the removal of the breasts, lymph nodes, and underlying muscle, often causing long-term pain and disability.3,5 In the 1920s, British surgeon Geoffrey Keynes challenged the need for such a radical technique and began using conservative surgery followed by radium treatment as an alternative to radical mastectomy.
Dr. Keynes’ work, followed by Robert McWhirter’s research one decade later, introduced the concept of simple mastectomy combined with radiotherapy as an alternative to Halsted’s procedure. Around the same time, Patey and Dyson from Middlesex Hospital in London introduced modified radical mastectomy.5 In the 1970s, Dr. Umberto Veronesi and his group conducted a controlled study to compare Halsted radical surgery to quadrantectomy with axillary dissection and radiotherapy. They demonstrated that there was no difference between the two groups in disease-free or overall survival.6,7 The first formal study in sentinel lymph nodes (SLN) of the breast was published by Giuliano et al in 1994.8 In their study they used a blue dye to localize the SLN and were able to localize it in 66% of the patients. Subsequently, several randomized trials showed that SLN biopsy without axillary dissection (ALND) was sufficient for staging breast cancer and for preventing regional recurrence in clinically node-negative breast cancer patients.9,10,11 These groundbreaking studies paved the way to current breast conservation therapies that allow for better quality of life without compromising survival.
Chemotherapy to treat predominantly hematologic malignancies became an option after World War II, but it wasn’t until the late 1960s that investigators began to use chemotherapy in advanced breast cancer.12 The first two randomized controlled trials for adjuvant chemotherapy (L-phenylalanine mustard [L-PAM] used alone carried out by Fisher et al and combination of cyclophosphamide, methotrexate, and 5-flurouracil [CMF] ran by Bonadonna et al) were conducted in the early 1970s and published in 1975 and 1976 respectively.13,14 These studies opened the door for subsequent studies in adjuvant treatment not only for breast cancer but for other cancer types. Over the years, new combination regimens were tested by different investigators in order to improve tolerance and outcome.
Pathology in breast cancer
The role of pathology has also changed significantly in the last 100 years from being purely diagnostic to providing prognostic and predictive information. Observations into the various forms of breast neoplasia led to the first classification of tumors of the breast by Fred Stewart and Frank Foote from Memorial Hospital, New York in 1946.15 The first grading system for breast carcinoma was introduced by Greenough in 1925.16 In 1957, the Scarff-Bloom-Richardson grading system for breast cancer was developed.17 In 1979, John G. Azzopardi at the University of London published his masterwork “Problems in Breast Pathology.”18 With the objective of providing a uniform nomenclature of human cancer, the “WHO Classification of Tumours project” (popularly known as the WHO Blue Books) started in 1956 and its first edition was published in 1967-1981. Since 2003, The International Agency for Research on Cancer (IARC), part of the World Health Organization, has continued this work of publishing and updating its classification as new knowledge is obtained over the years. This series is regarded as the gold standard for the diagnosis of tumors across the world.19
The TNM (tumor, node, metastases) classification of cancer, which is now in its 8th Edition, was developed between 1943 and 1952 by Prof. Pierre Denoix at the Institute Gustave-Roussy. Efforts in this project were led by Union for International Cancer Control (UICC). In 1987, the American Joint Committee on Cancer (AJCC) joined the UICC to unify staging systems into a single TNM system.20 Over the years, the classification has evolved as new discoveries in diagnostic, treatment, and prognosis of breast cancer are recognized and incorporated.
The development of histologic classification systems and the TNM standard for classifying the extent of spread of cancer were undoubtedly the basis for the modern era of breast cancer diagnosis and treatment and the era of personalized medicine. By the end of the twentieth century and the beginning of the twenty-first, molecular advances led to a better understanding of the differences in behavior among histologically similar cancer types. The search for markers of prognostic relevance in breast cancer was the focus of many twentieth century researchers. The discovery of the estrogen receptor in 1958 by Elwood Jensen, led to the first targeted therapy for breast cancer.21,22 By the 1980s, testing for the presence of estrogen receptor in breast cancer became standard, allowing the use of antiestrogen therapy such as Tamoxifen. The discovery of the tumor suppressor genes BRCA1 and BRCA2 in 1994 -1995 provided scientific basis for the concept that breast cancer could be hereditary.23,24 In the early 1980s, Robert Weinberg and his group discovered the HER2 gene.25 Soon afterwards, Dennis Slamon from UCLA discovered that the HER2 protein was present at high levels in about 30% of breast cancers and it was found to be linked with more aggressive breast cancer when overexpressed.26 Subsequent research in collaboration between Dr. Slamon’s team and Genentech led to the development of Herceptin (trastuzumab), an effective monoclonal antibody-based targeted therapy specifically designed to target HER2 receptors. In 2000, Perou et al described for the first time a molecular classification system for breast carcinoma, identifying 4 major intrinsic subtypes: ER-positive/luminal-like, basal-like, ERRB2-positive (HER2-enriched), and normal breast-like.27 This classification has been refined over the years and in addition to ensuing pivotal studies in this area, it led to a deeper understanding of tumor heterogeneity of breast cancer. Moreover, it was the basis for the commercially available gene expression profiling assays such as MammaPrint, Oncotype, and PAM50, used to stratify patients for therapy. These assays are nowadays an essential part of the daily practice of breast oncology.
In 2011, the EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) meta-analysis revealed that radiotherapy after breast-conserving surgery in patients with pathologically confirmed node-negative (pN0) or node-positive (pN+) disease leads to a 50% proportional reduction in overall recurrence by reducing or eradicating persistent locoregional disease.28 This benefit varies according to specific patient, risk of recurrence, and tumor characteristics underscoring the importance of multiple disciplines working together. Radiation therapy techniques has evolved significantly since their insertion with new treatment modalities focusing on not harming vulnerable organs/tissues such as the heart and lung as well as making the treatment less costly and more tolerable to patients. New regimens and techniques such as providing a radiation boost to the primary tumor site in certain high-risk cases, the use of accelerated whole breast irradiation (AWBI), accelerated partial breast irradiation (APBI), intraoperative radiation therapy (IORT), etc., has been developed.3
The evolution of screening and diagnostic modalities
Screening and diagnostic modalities have also evolved from the time of direct-exposure film-based mammography to current fully digitalized techniques.29 The benefits of screening mammography became apparent in the 1970s, and by the 1980s screening mammography had expanded significantly. Currently, other techniques such as ultrasound and magnetic resonance imaging are available as complements to mammography. These technological advances, together with published guidelines, standardized reporting systems, and research have taken the field of breast radiology from primarily diagnostic to procedural and key in providing necessary information for staging, prediction, and prognostication.
From the time BC was first mentioned in an ancient text from around 1600 BC found in 1860 in an Egyptian tomb,30 advances in science have allowed to a better understanding of BC and the introduction of effective treatments. Twentieth century’s scientific work in breast cancer led to twenty-first century era of personalized medicine. Discoveries in the areas of screening, diagnostics, pathology, molecular, treatment, prognosis, and quality of life has been too many to mention here. Understanding of tumor biology, molecular signatures, risk factors, surgical and medical therapies, and prognosis have made possible to personalize cancer therapies and predict survival. Fortunately, today most patients with breast cancer can go on to live a long and productive life. For those that we lose every year to this disease, we as physicians and scientists will continue working on improving quality of care and finding a cure.
Cancer Stat Facts: Female Breast Cancer. https://seer.cancer.gov/statfacts/html/breast.html
Todd M, Shoag M, Cadman E. Survival of women with metastatic breast cancer at Yale from 1920 to 1980. J Clin Oncol. 1983 Jun;1(6):406-8.
Boyages J, Baker L. Evolution of radiotherapy techniques in breast conservation treatment. Gland Surg. 2018;7(6):576-595.
Gold RH. The evolution of mammography. Radiol Clin North Am. 1992;30:1–19.
Freeman MD, Gopman JM, Salzberg CA. The evolution of mastectomy surgical technique: from mutilation to medicine. Gland Surg. 2018;7(3):308-315.
Veronesi, U et al. Comparison of Halsted mastectomy with quadrantectomy, axillary dissection, and radiotherapy in early breast cancer: long-term results Eur J Cancer Clin Oncol. 1986 22(9) 1085–9
Veronesi U et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast N Engl J Med. 1981 305(1) 6–11
Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220: 391–401
Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncology 2010; 11(10):927–933.
Krag DN Anderson SJ Julian TB et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol. 2007; 8: 881-888
Veronesi U Viale G Paganelli G et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg. 2010; 251: 595-600
DeVita VT Jr, Chu E. A history of cancer chemotherapy. Cancer Res. 2008 Nov 1;68(21):8643-53. doi: 10.1158/0008-5472.CAN-07-6611. PMID: 18974103.
Fisher B, Carbone P, Economou SG, et al. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. N Engl J Med 1975; 292: 110–22.PubMedGoogle Scholar
Bonadonna G, Brusamolino E, Valegussa P, et al. Combination chemotherapy as an adjunct treatment in operable breast cancer. N Engl J Med 1976; 294: 405–10.
Foote FW Jr, Stewart FW. A histological classification of carcinoma of the breast. Surgery 1946; 19:74–99.
Greenough RB . Varying degrees of malignancy in cancer of the breast. J Cancer Res 1925;9:425–463.
Bloom HJG, Richardson WW . Histological grading and prognosis in breast cancer. Br J Cancer 1957;11:359–377.
Azzopardi JG. Problems in breast pathology. In: Bennington JL, Ed. Major Problems in Pathology, Vol II. London: Saunders, 1979. Pp. 168–74.
WHO Classification of Tumours. Objective and Historical perspective. https://whobluebooks.iarc.fr/about/objective-and-historical-perspective/
TNM History, Evolution and Milestones. https://www.uicc.org/sites/main/files/atoms/files/TNM-History-2021.pdf
Lakhtakia R, Chinoy RF. A Brief History of Breast Cancer: Part II - Evolution of surgical pathology. Sultan Qaboos Univ Med J. 2014;14(3):e319-e322.
Jensen EV, DeSombre ER, Jungblut PW. Estrogen receptors in hormone responsive tissues and tumors. In: Wissler RW, Dao TL, Wood S Jr, Eds. Endogenous factors influencing host-tumor balance. Chicago: University of Chicago Press, 1967.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–92
Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513‐516.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177‐182.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumors. Nature (London) 2000; 406:747–52.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet. 2011; (published online Oct 20.)https://doi.org/10.1016/S0140-6736(11)61629-2
Joe BN, Sickles EA. The evolution of breast imaging: past to present. Radiology. 2014 Nov;273(2 Suppl):S23-44.
Faguet GB. A brief history of cancer: age-old milestones underlying our current knowledge database. Int J Cancer. 2015 May 1;136(9):2022-36.
Head of Breast Pathology