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Advances in Breast Cancer in the last 100 years: The Road from Radical Treatments to Personalized Medicine

Oct 17, 2022, 11:12 AM by Marilin Rosa

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. 

Conclusions 

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. 

References 

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