Triple-negative breast cancer, one of the most aggressive forms of the disease, has a bad reputation, and among socioeconomically disadvantaged black women, that reputation is especially well deserved.
In fact, according to Lisa A. Newman, MD, Director of the Breast Care Center, University of Michigan Comprehensive Cancer Center, among 156,570 subjects in the Women’s Health Initiative, the incidence of high-grade breast cancer was five times higher for black women than for whites. Mortality was higher for them as well. These were among the findings presented at the American Association for Cancer Research (AACR) 4th Annual Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held September 18–21 in Washington, DC.
Two other studies revealed a similarly skewed picture. The Carolina Breast Cancer Study reported increased prevalence of triple-negative breast cancer among premenopausal black women compared with postmenopausal women of the same race. The Southwest Oncology Group reported significantly worse outcomes in clinical trials for black women with triple-negative breast cancer molecular marker status than for whites.
Race Not the Only Factor
Dr. Newman added that international breast cancer studies are now revealing an even higher risk of triple-negative breast cancer among sub-Saharan African women than among American women of African descent.
She noted that poverty and lack of health insurance are the two major barriers to any type of health care, but they are especially common among black and Hispanic women. Other factors include inadequate screening, which results in delayed diagnosis, lifestyle, diet, environment, culture, and genetics. “Five-year survival is the lowest for the most impoverished women in American society,” she said.
These disparities have been well documented by the Surveillance, Epidemiology and End Results (SEER) program, the Centers for Disease Control and Prevention (CDC), and a variety of cancer registries, but the data are confounded by the fact that they rely on self-reporting of race and ethnic background. This means that an individual’s lineage might actually include contributions from several populations. “The racial composition of the United States is shifting toward increased diversity, so an improved understanding of the multifactorial etiology of health-care disparities is critical for improved cancer control,” Dr. Newman said.
Genetics and Treatment
James M. Ford, MD, Director of the Stanford Clinical Center Genetics Program, Stanford University School of Medicine, said that the genetics—and thus the treatment—of triple-negative breast cancer is still under investigation. The disease is a basal-like subtype that shares similar gene-expression profiles and DNA repair deficiencies with BRCA1-associated cancers. Those cancers exhibit sensitivity to gemcitabine, cisplatin, and poly (ADP-ribose) polymerase (PARP) inhibition. Therefore, he and his colleagues hypothesized that triple-negative breast cancer could be treated with these drugs.
They found that to be the case. Moreover, combination treatment indicated that PARP inhibition using small-molecule inhibitors or siRNA knockdown was synergistic with gemcitabine and cisplatin in triple-negative breast cancer cells but not in luminal cancer cells. This suggested that the synergistic effect of PARP inhibition and gemcitabine or cisplatin reflected underlying DNA repair defects.
“Thus, the sensitivity to combination treatment seemed to be mediated by sustained DNA damage and inefficient DNA repair,” Dr. Ford said. “This may be a new therapeutic strategy to treat triple-negative breast cancer, an aggressive disease that lacks effective treatment options.”
Other Markers and Treatments
Judy E. Garber, MD, Leader of the Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, echoed Dr. Ford’s thoughts. “We know that many factors contribute to the development of invasive breast cancer. The hormonal factors that have been studied for many years, like age at first period or use of hormone replacement, contribute to the development of hormone-driven breast cancers. We know much less about the risk factors for basal-like or ‘triple-negative’ breast cancers, over and above African-American ancestry, and little about risk factors for HER2-positive breast cancers. We have identified other genes that confer risk of breast cancer, and are finding that certain genes increase the risk of specific breast cancer subtypes, but inherited forms of breast cancer are uncommon, comprising no more than 5% to 10% of breast cancers overall.”
Regarding treatment, Dr. Garber said that efforts to understand the molecular biology—the genetic changes in the tumor cells—is leading to new treatments that target the cancer cells but spare the normal cells. Estrogen receptor and HER2 are examples of targets in some subsets of breast cancer. The problem with triple-negative breast cancer is the lack of one specific target, a “driver mutation or critical pathway” that is controlling the cancer cells in the majority of triple-negative tumors. Once those targets are identified, new agents can be developed to treat this difficult disease.
The Warburg Effect
In another study presented at the AACR meeting, investigators looked at premenopausal African-American women at high risk of breast cancer because of family history.
“We found that in a high proportion of high-risk African-American women, precancerous cells were taking in a high amount of glucose, and they also had activation of insulin signaling,” said Victoria L. Seewaldt, MD, Professor of Medicine and Co-Director of the Breast and Ovarian Cancer Program at Duke University. “In these women, we would worry that if they had developed gestational diabetes, the condition could stimulate precancerous cells.” It is thus desirable to detect this effect as early as possible, she noted.
“We see a lot of triple-negative breast cancer among young African-American women, and only 14% are alive 5 years after diagnosis,” Dr. Seewaldt said. “We already know that aggressive cancer cells actively consume glucose and produce lactic acid, even in the presence of adequate oxygen. The cells break down the glucose, thus stimulating growth. This is known as the Warburg effect.”
New research has indicated that the Warburg effect occurs earlier than previously thought, even during cancer initiation, in young African-American women. Dr. Seewaldt and colleagues theorized that it might be testable and looked at 77 high-risk premenopausal women, 45% of whom were African-American.
The signaling network most highly expressed in these women’s precancerous cells contained activated proteins associated with the Warburg effect (AKT/mTOR/P13K), insulin signaling (pACC, IRS-1), and epithelial-mesenchymal transition (interleukin‑6/STAT3/vimentin). This meant that if they developed gestational diabetes, the precancerous cells would be easily stimulated.
This is the first evidence that abnormal glucose uptake and the Warburg effect occurs during breast cancer initiation in high-risk African-American women. “We can now identify the pertinent signaling networks associated with the effect, which means that we are more likely to be able to provide early detection and prevention. To some extent, this risk can be mitigated by exercise, weight loss, and administration of metformin,” said Dr. Seewaldt. ■
Disclosure: Drs. Garber and Seewaldt reported no potential conflicts of interest.