Researchers from Fred Hutchinson Cancer Research Center and the Uganda Cancer Institute are launching a clinical study in the Ugandan capital, Kampala, that could change the way breast cancer in sub-Saharan Africa is diagnosed and treated.
The study will test a diagnostic tool that is already widely available throughout the continent to see if it performs as well as the method used in wealthier countries for determining a tumor’s hormone receptor status and other factors that guide treatment options. The study also will assess the feasibility of a three-drug chemotherapy regimen that patients will be able to take orally rather than intravenously.
Both the alternative tool and the oral therapy could have “potentially widespread application” in countries that are making gains against malaria, HIV/AIDS and other infectious diseases but have limited resources for diagnosing and treating cancer, said oncologist Dr. Manoj Menon. A researcher with Fred Hutch Global Oncology, Menon will co-lead the study with UCI director and oncologist Dr. Jackson Orem. Results are expected in about three years.
The study’s third objective is to use genetic sequencing to look for mutations that may explain why breast cancer in sub-Saharan Africa tends to strike younger women and to be especially aggressive — characteristics also seen in breast cancer in African-American women. Tumor tissue samples will be sent for analysis to the laboratory of University of Washington breast cancer geneticist Dr. Mary-Claire King, who discovered the “breast cancer gene,” BRCA1.
“Breast cancer is a huge problem in sub-Saharan Africa, but we don’t know much about the biology,” Menon said.
The breast cancer study builds on the decade-plus partnership between Fred Hutch Global Oncology and UCI and is funded by a $1.4 million grant from GSK as part of GSK’s Africa NCD Open Lab initiative. The Africa NCD Open Lab aims to support investigators within sub-Saharan Africa to conduct locally relevant clinical research to understand the unique attributes of non-communicable diseases, or “NCDs,” such as cancer, diabetes, and heart and lung diseases in African patients and to ensure that results from such research are shared for the benefit of the broader community.
“We are excited to collaborate on this project that could deliver important results to improve the scientific understanding and clinical approach to breast cancer in African patients,” said Dr. Mike Strange, vice president and head of GSK’s Africa NCD Open Lab.
Sub-Saharan Africa continues to struggle with communicable, or infectious, diseases, but international and regional efforts at prevention and treatment over the last decade have halved malaria deaths, and a rollout of antiretroviral drugs has begun to stem HIV deaths. Now cancer is emerging as a public health threat.
Breast cancer is one of the three most common cancers in sub-Saharan Africa, along with cervical and prostate cancers, and the second-leading cause of cancer deaths in women after cervical cancer, according to the World Health Organization. Fewer than half of those diagnosed with breast cancer in sub-Saharan Africa are still alive after five years, compared with almost 90 percent in the United States.
Various international and regional groups, including UCI, are working to raise awareness of breast cancer, eliminate the stigma associated with it and urge people to seek treatment sooner. The soon-to-launch study aims to improve care once they do.
“The GSK grant funding to undertake mutational profiling of breast cancer in Uganda allows us to describe the biology of our cancers and to take advantage of advancements in therapeutics of breast cancer and improve survival in our patients,” said the UCI’s Orem.
In the U.S. and other high-income countries, for example, breast tumors are analyzed to see whether they express certain receptors for the hormones estrogen and progesterone and for human epidermal growth factor. Targeted therapies (in addition to surgery, chemotherapy and radiation) are available for tumors that express those receptors.
Tumors that express none of those receptors are called triple negative. In the U.S., African-American women are more likely to be diagnosed with triple-negative breast cancer and have a 40 percent higher death rate than European-American women. Triple negative breast cancer is particularly aggressive and has a poorer prognosis than other breast cancers, in part because there are no targeted therapies, underscoring the need for more research into this type of cancer and the importance of including different races and ethnicities in clinical trials.
No one now knows which tumor receptors are prevalent in sub-Saharan Africa because in most countries, reliable analysis is not done. Two small studies in Uganda have shown conflicting results.
Part of the problem is a lack of resources and training to do the analysis. The gold standard for determining receptor status, at least in developed countries, is known as an immunohistochemistry test. However, barriers to testing include costs, inexperience in preparing specimens properly and a dearth of pathologists trained to reliably interpret the results.
The UCI-Fred Hutch study will test an alternative diagnostic tool — reverse transcription polymerase chain reaction, or RT-PCR — which already is used throughout the continent as part of international and regional efforts to test and treat HIV. Smaller studies have compared RT-PCR testing against immunohistochemistry to test for breast cancer receptor status. The two tests resulted in identical results about 90 percent of the time.
The study will enroll 100 Ugandan women with newly diagnosed breast cancer to undergo additional analysis of receptor status. Their tumor samples will be processed in the laboratories of the UCI-Fred Hutch Cancer Centre in Kampala, a state-of-the-art facility that opened in 2015 with outpatient clinics, laboratories and classrooms for training researchers and clinicians. The Kampala lab will ship frozen tissue samples to Seattle, and the study will compare the results of samples tested in Kampala using RT-PCR and in Seattle using immunohistochemistry.
In addition, the next-generation sequencing done at King’s Seattle laboratory by study co-investigator Dr. Eric Konnick — also using samples processed by the UCI-Fred Hutch laboratories in Kampala — will seek to understand at the molecular level why breast cancer in Uganda is so aggressive and why it so often affects young women. Konnick will focus on the exome, or the small percentage of the billions of nucleotides in the human genome that have the potential to be “expressed,” or translated into proteins.
“We do know that breast cancer tends to be more aggressive in Uganda,” Menon said. “But there are other differences too. The average age of a breast cancer patient at UCI is in the 40s, where in the U.S., it is 61. There’s likely something different in the pathogenesis of the disease. Hopefully this study will help to clarify some of the differences.”
In addition to establishing whether RT-PCR is an effective alternative to immunohistochemistry, the study will also test the feasibility of a chemotherapy regimen already shown to be effective for estrogen-positive breast cancers. Of the 100 women enrolled in the trial, 25 with receptor-positive early or locally advanced stage breast cancer will be invited to participate in this part of the study.
Menon and Orem worked with Fred Hutch oncologist and clinical researcher Dr. V.K. Gadi to develop an all-oral regimen using three drugs that are available in sub-Saharan Africa — cyclophosphamide, methotrexate and fluorouracil, or CMF.
Although the UCI-Fred Hutch Cancer Centre has infusion rooms for delivering intravenous chemotherapy, such resources are scarce in many African countries. An oral regimen is less expensive, easier to administer and avoids risks inherent to IV therapy, starting with potential infections from breaking the skin to insert needles or ports.
Researchers also hope that oral therapy will make it more likely for patients to complete all six cycles of therapy — which, with IV chemotherapy, can be a challenge given the time required and transportation barriers to get to a cancer center. As an example, Menon pointed to children being treated for Burkitt lymphoma, a fast-growing tumor that is the leading cause of pediatric cancer deaths in sub-Saharan Africa. The cancer is curable if treated early enough, but 40 percent of young patients do not complete the full six cycles of IV infusions, he said.
“Our hope is that an oral regimen for breast cancer will decrease patient abandonment and increase patient benefit,” Menon said. “Dr. Orem worked on oral chemotherapy for non-Hodgkin lymphoma, so he is very interested in developing oral regimes because of their widespread applicability.”
Following treatment, patients with estrogen-receptor positive tumors will receive tamoxifen — a targeted treatment for estrogen-positive tumors — daily for five years. Today, some physicians in Uganda prescribe tamoxifen even if they do not know the patients’ receptor status; because the drug is relatively inexpensive and has few side effects, they reason that it can’t hurt and may help.
The trouble is, in Uganda as in many poor countries, there sometimes is not enough of any kind of medication, including tamoxifen, to go around. If the study shows that RT-PCR reliably determines tumor receptor status, physicians could make sure that this scarce resource is used only for patients who will benefit.
“We’re hoping this testing will help demonstrate which women can better utilize a medication when resources are limited as well as prevent harm in those women who will not derive a benefit from estrogen-targeted medications,” Menon said.
U.S. patients may benefit as well, he added, in situations where immunohistochemistry may not be available or patients would better adhere to oral chemotherapy than an IV regimen. Comparing the molecular profile of Ugandan tumors to those in African Americans may also yield insights into why breast cancer is so aggressive in these populations.
In addition to Menon, Orem, Konnick and Gadi, Dr. Nixon Niyonzima, a Ugandan physician who recently received his doctorate in molecular and cellular biology from Fred Hutch and UW, will be involved in running the trial in Kampala.
Contributing advice on the study were former Global Oncology director Dr. Corey Casper and Fred Hutch researchers Drs. Ben Anderson, Julie Gralow, and Peggy Porter, who are involved in global breast cancer research and in developing resource-sensitive, culturally appropriate interventions. Leukemia researchers and diagnostic experts Drs. Jerry Radich and Olga Sala-Torra also advised on the project.
Menon acknowledges that the study will not change — at least directly — one of the key obstacles to treating breast cancer in sub-Saharan Africa: the late stage at which women seek help. But if better diagnosis and easier-to-complete oral chemotherapy leads to additional years of health, word would spread and women might feel encouraged to come in earlier.
“What this study can do is provide information that can make a more confident diagnosis that will impact therapeutic options,” Menon said. Among those options is not just the full six cycles of chemotherapy but the possibility of using additional targeted therapies such as trastuzumab (Herceptin) for patients whose tumors are positive for human epidermal growth receptor.
The announcement of the GSK-funded study comes at a proud moment for the UCI: It will mark its 50th anniversary next week with a two-day scientific symposium in Kampala. Founded in 1967 with the support of the U.S. National Cancer Institute as the Lymphoma Treatment Centre, today the UCI is the sole cancer facility serving five East African countries.
“The GSK grant enables us to continue to develop our capacity to conduct basic and translational research,” said Orem. “We are grateful to GSK for this funding opportunity and to Fred Hutchinson Cancer Research Cancer, our partners on this study and our long-standing collaborators who are helping us build and strengthen research capacity at the UCI.”
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.