Over the last several decades, the survival rate for most kinds of breast cancer have increased due to earlier detection, new targeted therapies, and combination treatment modalities. As we’ve discussed before at Oncobites, cancer is not a single disease. It turns out that multiple distinct subtypes exist even within the category of “breast cancer”. The most common subtype of breast cancer is driven by the hormone estrogen and the expression of the estrogen receptor (these are often referred to as estrogen receptor positive, or ER+). For estrogen-driven breast cancers, the prescribed therapy may include drugs to block estrogen signaling to the cancer cells (hormone therapy) with or without chemotherapy. While chemotherapies are responsible for prolonging the lives of many cancer patients, they are also responsible for many unpleasant side effects. Chemotherapy works by targeting rapidly dividing cells and killing those cells by damaging their DNA or blocking the cellular processes that cells use to repair damaged DNA. Cancer cells are typically very rapidly dividing, so they are preferentially targeted by chemo, but so are normal, healthy, rapidly dividing cells like developing blood cells, the cells that line the inside of your mouth and gut and famously, hair follicles. While hair loss is the most visible side effect of chemotherapy, the other effects of chemo on healthy cells can lead to nausea, fatigue, anemia, cognitive changes, and other symptoms that significantly decrease patients’ quality of life. Though many of these side effects are short-term, chemo can also cause long-term damage to organs like the heart and kidneys and, rarely, can even contribute to the development of secondary cancers.
Chemotherapy has clear benefits in the treatment of cancer but also has obvious risks so it should be used only when appropriate. So how do doctors know what patients are appropriate to treat with chemo? In the last 15 years, physicians have been able to harness advances in DNA sequencing technology (and a decrease in the cost of sequencing) to identify important mutations in tumors. There are now multiple tests that doctors can use to tell whether their patients’ tumors have mutations in a panel of prognostic genes. Using these tests, doctors can stratify patients into one of three risk categories by the probability that their estrogen-driven breast cancer will progress or return after being treated. After years of studying these patient populations and their response to treatment, doctors have determined that low-risk patients only need to be treated with hormone therapy, whereas high-risk patients do better when treated with hormone therapy and chemotherapy. However, the best treatment for mid-risk patients has long remained a mystery. If mid-risk tumors behave more like high-risk tumors, then these patients should be treated with both chemotherapy and hormone therapy. However, if these tumors are more like low-risk tumors, treating these patients with chemotherapy means exposing them to unnecessary side effects. So what is the best course of action for patients with middle-risk tumors?
To answer this question, a large, prospective clinical trial of women with ER+ breast cancer randomized 6,711 middle-risk patients to receive either hormone therapy or hormone therapy plus chemotherapy (the low and high-risk patients in the cohort were treated with hormone therapy or hormone therapy plus chemo, respectively). These patients were then followed for an average of 7.5 years. The authors found that for the midrange risk group there was no difference between those that received only hormone treatment and those that received both chemo + hormone treatment for all measured endpoints. In clinical trials, endpoints are the measured outcomes for patient health and disease progression. In this study, the authors measured disease-free survival, disease recurrence, occurrence of a second primary cancer, and overall survival and found no differences in these measures for the mid-risk groups treated with hormone therapy alone or with the addition of chemo.
So what does this mean for patients? The results of this study suggest that for these specific groups, women with ER+ breast tumors are determined to be of low or intermediate risk, the most common subgroups of breast cancer, hormone therapy alone works just as well as hormone therapy in combination with chemotherapy. Eliminating unnecessary chemotherapy for the mid-risk group could have major repercussions for increasing the quality of life for these patients, as well as decreasing costs to the healthcare system.
Sparano, J. A., Gray, R. J., Makower, D. F., Pritchard, K. I., Albain, K. S., Hayes, D. F., . . . Sledge, G. W., Jr. (2018). Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. doi: 10.1056/NEJMoa1804710
Breast Cancer Cells, Dr. Cecil Fox (Photographer), National Cancer Institute, National Institutes of Health