The gist: A drug called pembrolizumab (aka Keytruda or MK-3475) has shown promise for people with metastatic triple-negative breast cancer (TNBC) whose tumors have high levels of a protein called PD-L1. It was recently tested in patients in a clinical trial. Pembrolizumab is already approved by the U.S. Food and Drug Administration (FDA) for treating melanoma. It is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. More research will determine just how well pembrolizumab might work for TNBC.
“In patients with metastatic triple-negative breast cancer—a disease with no approved targeted therapies—infusion of pembrolizumab produced durable responses in almost one out of five patients enrolled in a phase-Ib clinical trial, according to data presented Dec. 10, at the 2014 San Antonio Breast Cancer Symposium.
“The multi-center, non-randomized trial was designed to evaluate the safety, tolerability and antitumor activity of bi-weekly infusions of pembrolizumab (MK-3475, marketed as Keytruda®). The researchers enrolled 27 patients, aged 29 to 72 years, who had metastatic triple-negative breast cancer that either relapsed after treatment for early stage disease or progressed on therapy for advanced disease.
” ‘For this group of patients our treatment options are limited to chemotherapy,’ said study director Rita Nanda, MD, assistant professor of medicine and associate director of the breast medical oncology program at the University of Chicago.
“All patients in the study had triple-negative tumors with high levels of a protein called programmed death-ligand 1 (PD-L1). This protein can suppress the immune system’s efforts to eliminate cancer cells. Pembrolizumab is a monoclonal antibody designed to help reactivate a person’s own immune system to help fight the tumor.”
The gist: This article discusses a potential way to improve chemotherapy treatment for triple-negative breast cancer (TNBC), but it has only been tested in mice so far, so it is not yet known whether it would work for humans. The method would use drugs called HIF inhibitors to make breast cancer cells more responsive to chemotherapy. HIF inhibitors are already being used in humans with other conditions, so clinical trials may soon be able to show whether they work for TNBC.
“Triple-negative breast cancer is as bad as it sounds. The cells that form these tumors lack three proteins that would make the cancer respond to powerful, customized treatments. Instead, doctors are left with treating these patients with traditional chemotherapy drugs that only show long-term effectiveness in 20 percent of women with triple-negative breast cancer. Now, researchers at The Johns Hopkins University have discovered a way that breast cancer cells are able to resist the effects of chemotherapy—and they have found a way to reverse that process.
“A report of their findings was published online in the journal Proceedings of the National Academy of Sciences on Dec. 1.
“Triple-negative breast cancers account for about 20 percent of all breast cancers in the United States, and 30 percent of all breast cancers in African-American women. In addition to being resistant to chemotherapy, they are known to include a high number of breast cancer stem cells, which are responsible for relapses and for producing the metastatic tumors that lead to the death of patients with cancer. Previous research revealed that triple-negative breast cancer cells show a marked increase in the activity of many genes known to be controlled by the protein hypoxia-inducible factor (HIF). Given these past results, a research team directed by Gregg Semenza, M.D., Ph.D., decided to test whether HIF inhibitors could improve the effectiveness of chemotherapy.”
The gist: New research shows that triple-negative breast cancer (TNBC) patients who have a particular molecule called miR-21 near their tumor, but not actually in the tumor cells, have worse clinical outcomes. This opens up the future possibility that doctors could check for miR-21 in order to better understand a patient’s disease and make treatment decisions.
” ‘Triple-negative’ breast cancer (TNBC) occurs in patients whose cells do not express receptors for estrogen, progesterone, and/or human epidermal growth factor receptor 2 (ER-/PR-/HER2-). Because of the absence of these predictive biomarkers, treatment assignment can be difficult. Now, researchers report that high levels of the microRNA miR-21 in the tumor microenvironment, but not in the tumor epithelia (cancer cells), are associated with worse clinical outcomes for patients with TNBC, thus identifying a possible TNBC prognostic biomarker, according to a study in The American Journal of Pathology.
“TNBC accounts for 15% to 20% of breast cancer cases, and patients have shorter recurrence-free survival (RFS) and breast cancer-specific survival (CSS) relative to other major subgroups. It is likely that different subtypes of TNBCs exist, and the heterogeneity may be responsible for a wide variation in response to treatment. ‘Predictive biomarkers for therapeutic response prediction and novel therapeutic targets that address distinct biological features of TNBC subgroups are needed for these patients,’ says Lorenzo F. Sempere, PhD, head of the Laboratory of microRNA Diagnostics and Therapeutics at Van Andel Research Institute in Grand Rapids, MI. ‘These findings add support to the growing importance of miRNA-based diagnostics.’ “
“Most patients with triple-negative breast cancer should undergo genetic testing for mutations in known breast cancer predisposition genes, including BRCA1 and BRCA2, a Mayo Clinic-led study has found. The findings come from the largest analysis to date of genetic mutations in this aggressive form of breast cancer. The results of the research appear in the Journal of Clinical Oncology.
” ‘Clinicians need to think hard about screening all their triple-negative patients for mutations because there is a lot of value in learning that information, both in terms of the risk of recurrence to the individual and the risk to family members. In addition, there may be very specific therapeutic benefits of knowing if you have a mutation in a particular gene,’ says Fergus Couch, Ph.D., professor of laboratory medicine and pathology at Mayo Clinic and lead author of the study.
“The study found that almost 15 percent of triple-negative breast cancer patients had deleterious (harmful) mutations in predisposition genes. The vast majority of these mutations appeared in genes involved in the repair of DNA damage, suggesting that the origins of triple-negative breast cancer may be different from other forms of the disease. The study also provides evidence in support of the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing of triple-negative breast cancer patients.
“Triple-negative breast cancer is a specific subset of breast cancer that makes up about 12 to 15 percent of all cases. The disease is difficult to treat because the tumors are missing the estrogen, progesterone and HER-2 receptors that are the target of the most common and most effective forms of therapy. However, recent studies have suggested that triple-negative breast cancer patients might harbor genetic mutations that make them more likely to respond to alternative treatments like cisplatin, a chemotherapy agent, or PARP inhibitors, anti-cancer agents that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes.”
“Breast cancer patients of Mexican descent who had a family history of breast or ovarian cancer were almost twice as likely to have triple-negative breast cancer than other subtypes of breast cancer, according to data presented at the American Association for Cancer Research (AACR) conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Nov. 9–12.
” ‘Triple-negative breast cancer is one of the worst breast cancer subtypes in terms of outcomes,’ said Maria Elena Martinez, PhD, the Sam M. Walton endowed chair for cancer research and a professor in the Department of Family and Preventive Medicine at the University of California San Diego Moores Cancer Center in La Jolla. ‘So, our finding that family history is related to breast cancer subtype for Hispanic women of Mexican descent has tremendous implications for breast cancer treatment, screening, and prevention among this population. It not only affects decisions around treatment plans for patients, but extends to screening and prevention plans for family members.
” ‘Before our study, we knew very little about the factors that affect Hispanic/Latina women’s risk for breast cancer,’ Martinez continued. ‘The Ella Binational Breast Cancer Study was initiated to try and address this issue for Hispanic women of Mexican descent.’ “
“The cancer drug eribulin, originally developed from sea sponges, could give women with advanced triple negative breast cancer an average of five extra months of life, according to research presented at the National Cancer Research Institute (NCRI) Cancer Conference in Liverpool.
“Researchers led by Professor Chris Twelves, based at the University of Leeds and Leeds Teaching Hospitals NHS Trust, looked at two major clinical trials of more than 1,800 women with breast cancer that had started to spread to other parts of the body. The phase III trials – the final stage of testing before deciding whether a drug can be prescribed to patients – compared the survival of women treated with eribulin* to those given standard treatment.
“The two studies showed an overall improvement in survival of more than two months for women treated with eribulin**. The most significant improvement was seen in women with the advanced triple negative form of breast cancer, where there are limited treatment options; these women’s survival improved by nearly five months. There was also a survival boost of more than two months for women with the HER2 negative form of breast cancer***.
“Cancer spreading to other organs – called metastasis – is responsible for around 90 per cent of all cancer deaths. And, when patients with breast cancer are diagnosed after the disease has started to spread, 10-year survival is around one in 10, compared to nearly nine in 10 for those diagnosed at the earliest stage.
“Study author, Professor Chris Twelves, said: ‘Our results show a substantial improvement in survival for women with metastatic triple negative breast cancer, and a more modest, but significant, benefit for those with HER2 negative breast cancers.’
“ ‘Eribulin has previously been offered to women who’ve already been through several lines of chemotherapy. But the European Union has recently approved eribulin for patients who have received less treatment for their breast cancer, which means we hope to give more patients another treatment option in the not-too-distant future.’ “
“A large collaborative study provides new evidence that African-American women may be able to significantly reduce their risk of developing aggressive forms of breast cancer by breastfeeding. The study, published online ahead of print in the Journal of the National Cancer Institute, is based on a collaborative research effort led by researchers at Roswell Park Cancer Institute (RPCI), Boston University’s Slone Epidemiology Center and the University of North Carolina Lineberger Cancer Center.
“African-American women have a disproportionately high incidence of two aggressive forms of the disease: estrogen-receptor-negative (ER-negative) and triple-negative breast cancer, in which tumor cells test negative for three key hormone receptors. Earlier studies have shown a connection between the number of times a woman has given birth, or parity, and increased risk of ER-negative tumors, and that breastfeeding reduced risk of these aggressive breast cancers, but this large new study provides the most conclusive evidence to date of these connections.
“Researchers from the three institutions formed the AMBER Consortium, or African American Breast Cancer Epidemiology and Risk Consortium, by combining four epidemiologic studies with large numbers of African-American participants: the Black Women’s Health Study (BWHS), Multiethnic Cohort Study (MEC), Carolina Breast Cancer Study (CBCS) and Women’s Circle of Health Study (WCHS).”
“Women who have had children (parous women) appear to have an increased risk of developing estrogen receptor-negative breast cancer, the subtype that carries a higher mortality rate and is more common in women of African ancestry. A similar relationship was found for triple-negative breast cancer. However, the association between childbearing and increased risk of estrogen receptor-negative and triple-negative breast cancer was largely confined to the women who had never breastfed. These findings, published in the Journal of the National Cancer Institute, suggest that low rates of breastfeeding in African American women may contribute to their higher incidence of the more aggressive and difficult-to-treat subtypes of breast cancer.
“Researchers from Boston University’s Slone Epidemiology Center (SEC) collaborated with the Roswell Park Cancer Institute of Buffalo, NY and the University of North Carolina Lineberger Cancer Center to form a consortium to study the determinants of breast cancer subtypes in African American women. They combined data on breast cancer cases and controls from four large studies, including the Boston University Black Women’s Health Study. The combined analyses included 3,698 African American women with breast cancer, including 1,252 with the estrogen receptor-negative subtype.
“They found that parous women had a 33 percent higher chance of developing estrogen receptor negative breast cancer than women who had never given birth. Women who had four or more births and had never breastfed any of their babies had a 68 percent higher chance of developing this type of cancer compared with women who had only one birth and had breastfed that baby. By contrast, parous women who had four or more births had a slightly decreased risk of estrogen receptor-positive breast cancer, regardless of whether or not they had breastfed.”
“Because of its rapid growth rate, many women with triple-negative breast cancer receive chemotherapy to try to shrink it before undergoing surgery. With the standard treatment, the cancer is eliminated from the breast and lymph nodes in the armpit before surgery in about one third of women. This is referred to as a pathologic complete response (pCR). In patients who achieve pCR, the cancer is much less likely to come back, spread to other parts of the body, and cause the patient’s death than if the cancer survives the chemotherapy.
“Sikov and his collaborators studied the addition of other drugs – carboplatin and/or bevacizumab – to the standard treatment regimen to see if they could increase response rates. More than 440 women from cancer centers across the country enrolled in this randomized clinical trial.
” ‘Adding either of these medications significantly increased the percentage of women who achieved a pCR with the preoperative treatment. We hope that this means fewer women will relapse and die of their cancer, though the study is not large enough to prove this conclusively. Of the two agents we studied, we are more encouraged by the results from the addition of carboplatin, since it was associated with fewer and less concerning additional side effects than bevacizumab,’ Sikov explains.”
Editor’s note: This article describes the results of a clinical trial—a research study with volunteer patients.