"Everything should be made as simple as possible, but not simpler."
Albert Einstein

These 11 words may or may not have been said by Einstein in this precise order. However, he and many others throughout intellectual history have expressed the same idea. Nature is complex; but much about it can be understood. The physical laws that apply to things on the earth are universal. Ecosystems are dynamic and adaptive to environmental changes, within limits, but can be destroyed by natural and man-made disasters. Nucleic acids encode information that directs development, form, and function of all living things on earth. These are generalizations that help shape our view of our world.
As much as elements and mechanisms of life are shared among living things, every person is unique. Physicians recognize the wide range of physiologic and pathologic diversity among the people whom they manage. However, progress in the cure and management of disease up to now has come from reductionism, attempting to find what is common among people and illness rather than emphasizing distinctions among them. An unavoidable consequence is that physicians oversimplify complexity, largely because we do not fully understand the influence of all of the variables on the patient and the course of the disease.
Despite its limitations, reductionism has helped us make genuine progress in the treatment of many diseases. Peptic ulcer disease is now treated with antibiotics. Cancers are being prevented by vaccination against the viruses that cause them (hepatitis B and hepatoma; human papillomavirus and cervical cancer). More than 90% of children with many forms of cancer are now cured based on therapeutic progress painstakingly made through reductionist thinking. Nevertheless, experienced clinicians have long recognized that our labels tend to lump together heterogeneous entities.
In the middle of the 20th century, about five lymphoid malignancies were recognized: myeloma, Hodgkin’s disease, follicular lymphoma, acute lymphoid leukemia, and chronic lymphoid leukemia. The most common form of lymphoma, diffuse large B-cell lymphoma, was thought to be a reticulum cell sarcoma. With the application of modern tools of genetic analysis, immunologic phenotyping, and more sophisticated microscopic analysis, together with clinical recognition of particular features occurring more commonly in certain patients, it is now recognized that there are nearly 40 different kinds of lymphoid malignancy. Diseases that were formerly not recognized or were lumped together with other diseases are now being studied as separate entities, and new and better and more specific treatments are being developed. So it also has been with other cancers.
Breast cancer has been known to be a heterogeneous disease entity for more than 100 years. In 1895, George Beatson discovered that removing the ovaries from one of his patients caused her breast cancer to regress. Efforts to expand on these findings revealed that only a minority of women responded to oophorectomy with tumor shrinkage. In the 1950s, Elwood Jensen identified estrogen receptor expression on some breast cancers and noted that patients with tumors expressing estrogen receptors were much more likely to respond to hormonal therapies, and those whose tumors did not express estrogen receptors were highly unlikely to respond to hormonal therapy. For 30 years thereafter, breast cancer was recognized as at least two diseases, estrogen receptor positive breast cancer and estrogen receptor negative breast cancer.
In the late 1980s, a new marker was recognized that further subdivided patients with breast cancers: HER-2. And then there were four types of breast cancer; ER+ HER-2+, ER+ HER-2–, ER– HER-2+, and ER– HER-2–. This distinction was useful because trastuzumab, an antibody to HER-2, was found to reduce recurrences of HER-2+ breast cancer by about 50% when employed as a component of adjuvant therapy. More heterogeneity was introduced by the recognition of familial forms of breast cancer due to alterations in BRCA1 and BRCA2.
Science marches on. We are moving in the direction of defining important characteristics of each woman’s tumor and providing her with therapy that is most likely to benefit her. Substantial progress has resulted. Not only are the applied therapies more likely to work but also many women are spared the toxicity of therapy that had very low likelihood of being helpful.
It is now possible to examine gene expression in breast tumors, and doing so has identified even more heterogeneity. In this issue of Hot Topics in Oncology, Sotiriou and his colleagues review the results of analysis of gene expression profiles of breast cancer. Five types are now recognized, based on the patterns of gene expression in nonmalignant breast cells. These include normal (or normal-like), luminal A, luminal B, HER-2 overexpressing, and basal or basal-like breast cells. In addition, commercially available assays are now available for gene signatures to help define prognosis, identify vulnerabilities to specific interventions, and recognize in advance treatments highly unlikely to be useful. Sotiriou and colleagues review what is known about these molecular tools and how they can be used to assist the physician in managing patients.
These molecular groupings have allowed clinicians to retrospectively examine their patients and the courses of their cancers, and from this analysis, new clinicopathologic entities have been defined. An important new entity is so-called triple-negative breast cancer, named on the basis of the absence of estrogen receptor, progesterone receptor, and HER-2 expression. Andreopoulou and Hortobagyi review the treatment of hormone receptor negative breast cancer in general and discuss triple-negative breast cancer in some depth.
This issue of Hot Topics in Oncology is rich in valuable new information that refines our view of breast cancer and assists in developing the best possible therapeutic approach to our patients.