About three-quarters of breast cancers, the most common cancer in women in the U.S., are estrogen hormone dependent. Patients with this type of breast cancer are initially treated with drugs that block estrogen, such as Tamoxifen. However, one-third to half of these patients eventually become resistant to this treatment. For these patients and those whose tumors are not estrogen dependent to begin with, there are no alternative hormone treatment options.
In a new study directed by Tan A. Ince, M.D., Ph.D., associate professor of pathology at the University of Miami Miller School of Medicine and member of the Sylvester Comprehensive Cancer Center, researchers have developed a new breast cancer classification system that shifts the focus away from genetic mutations, a common approach of mainstream cancer research, but one that has been less effective than first imagined. The findings of this study, published online in the Journal of Clinical Investigation, offer a new approach to treating breast cancer, by using normal tissue and hormone receptors as a guideline to determine effective therapies.
In recent years, scientists have concentrated on identifying genetic mutations within breast cancers with the goal of developing a targeted therapy for each mutation. The clinical problem is that the average breast cancer has more than 200 mutations, and most patients share few, if any, commonalities. Researchers have believed that tumors differ from normal tissue, but Ince and the other team members found that not to be the case. "Everyone has just been studying tumors," said Ince. "They haven't been comparing normal tissue and tumors to this degree."
Ince, working with first author of the study Sandro Santagata, M.D., Ph.D., from Brigham and Women's Hospital, Harvard Medical School, and a team of researchers from both institutions found that about three-quarters of estrogen-dependent tumors and two-thirds of estrogen-independent tumors expressed hormone receptors for vitamin D and testosterone. The researchers showed that treatment of breast cancer cells with hormones that activate vitamin D and testosterone receptors reduced the growth of cancer cells. In addition, these hormones increased the efficacy of standard chemotherapy.
"These findings offer the possibility of expanding hormone therapy to patients who are otherwise treated with chemotherapy," said Ince, who is also a member of the Braman Family Breast Cancer Institute at Sylvester. With further work, he theorizes that it may also allow using lower doses of chemotherapy with the same effect and serve as a useful prognosticator.
Ince, who is a breast pathologist and cancer pharmacologist, began this study more than 10 years ago with funding from the Breast Cancer Research Foundation and meticulously described normal cell types in human breast tissue. Following on this lead, the research group eventually studied more than 15,000 normal breast cells and discovered 11 previously undefined normal cell subtypes. They grouped these 11 normal breast cell types into four new hormonal differentiation groups (HR 0, 1, 2, 3), which were characterized by vitamin D, androgen and estrogen hormone receptor expression.
In evolutionary biology, the ancestry of each species is determined based on key features that are inherited. Using this evolutionary principle, Ince constructed a tree of life for normal human breast cells. Next, the researchers took this information and compared it against 3,157 human breast tumors of patients and found that each patient's tumor could be placed precisely in this tree. Moreover, the tumors could also be grouped into four new hormonal differentiation groups (HR 0, 1, 2, 3), which were characterized by vitamin D, androgen and estrogen hormone receptor expression.
Importantly, the patients in different HR groups had different survival rates and responses to hormone treatments. The researchers found that nearly half of the breast cancer patients were in the HR3 group, meaning these patients' tumors had all three hormone receptors (estrogen, testosterone and vitamin D). Patients with these triple HR-positive tumors (HR3) were up to seven times more likely to survive compared with patients with triple HR-negative tumors (HR0). Compared with many existing genetic/molecular tests with 2-3 fold survival differences, "this cell-type based approach can become a powerful new tool in predicting patient outcomes," said Ince.
Since none of the existing genetic tests identify the HR0-3 subgroups, this will require translating the findings in this study into a clinically available new test. Additionally, description of these HR cell types raises the possibility of cell-targeted therapies. For example, with further work these findings could be translated into the clinic as triple hormone therapy for HR3 tumors. Hence, these studies may lead to cell-based diagnosis and treatment options as an alternative to gene-based approaches.
In this study the researchers also found that some of the standard breast tumor subtypes previously identified, called basal-like carcinoma, have been labeled erroneously due to incorrect classification of normal cell types.
Follow-up studies are underway in Ince's laboratory in collaboration with other researchers at Sylvester to translate these findings to the clinic.