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Tuesday, July 9, 2019

Study Confirms Disparities in Triple-Negative Breast Cancer Diagnoses

A new study published early online in the journal Cancer shows that women of color and young women may face elevated risks of developing triple-negative breast cancers, which are often aggressive and do not respond to hormone therapy or targeted therapy (2019; https://doi.org/10.1002/cncr.32207).

Previous U.S. studies have found racial disparities in triple-negative breast cancer diagnoses, but few have looked beyond the scope of one state. To conduct a larger study, Lia Scott, PhD, MPH, of the Georgia State University School of Public Health, and her colleagues analyzed all breast cancer cases diagnosed during 2010-2014 from the United States Cancer Statistics database, a population-based surveillance system of cancer registries with data representing 99 percent of the U.S. population.

The team identified 1,151,724 cases of breast cancer from 2010 to 2014, with triple-negative cases accounting for approximately 8.4 percent of all cases. The researchers uncovered a significant burden of triple-negative breast cancer for women of color, specifically non-Hispanic black women, and for younger women.

Compared with non-Hispanic white women, non-Hispanic black women and Hispanic women had 2.3-times and 1.2-times higher odds of being diagnosed with triple-negative breast cancer, respectively. More than 21 percent of non-Hispanic black women were diagnosed with triple-negative breast cancer, compared with less than 11 percent for all other types of breast cancer. Women younger than 40 years of age had twice the odds of being diagnosed with triple-negative breast cancer than women aged 50-64 years. Also, among women who were diagnosed with breast cancer, those diagnosed at late stages were 69 percent more likely to have triple-negative cancer than other types.

The authors noted that, due to the aggressive nature of triple-negative breast cancer and the lack of therapeutic options, it is important to know which individuals face a higher risk and what factors may influence this risk.

"With the advent and availability of more comprehensive cancer data, such as the United States Cancer Statistics database, it is important that we continue to explore disparities in order to better inform practice and policy around screenable cancers like breast cancer," Scott noted. "We hope that this update on the epidemiology of triple-negative breast cancer can provide a basis to further explore contributing factors in future research."

Tuesday, July 9, 2019

Knowing BRCA Status Associated With Better Breast Cancer Outcomes

Ashkenazi Jewish women have a 1-in-40 chance of carrying the BRCA mutation and these BRCA-positive women have an 80 percent lifetime risk of developing breast or ovarian cancer. A study by University of Colorado Cancer Center and Shaare Zedek Medical Center, Israel, presented at the European Society of Human Genetics Annual Meeting 2019 shows the importance of healthy women knowing their BRCA status, even when these women choose not to undergo prophylactic mastectomy.

Of 63 Ashkenazi Jewish women unaware of their BRCA+ status at the time of breast cancer diagnosis, and 42 women who were aware they were BRCA+ prior to their breast cancer diagnosis (but had decided against surgical prevention), the women who knew their BRCA+ status were diagnosed with earlier-stage breast cancer, needed less chemotherapy, less extensive axillary surgery, and had greater overall 5-year survival (98% vs. 74%).

"The problem is that genetic screening for BRCA by a saliva or blood test is not recommended by any medical body or health care organization in healthy Ashkenazi Jewish women without a strong family history. Therefore, the way women usually find out they have the BRCA gene is only after they are diagnosed with breast cancer, at which time we've lost the opportunity to offer surgery that could prevent breast cancer or start high-risk breast cancer screening at an age young enough to detect cancers earlier," explained Rachel Rabinovitch, MD, FASTRO, CU Cancer Center investigator and Professor in the CU School of Medicine Department of Radiation Oncology.

The BRCA genes, BRCA1 and BRCA2, are tumor-suppressor genes, meaning that their function is to identify and correct genetic mistakes that could lead to cancer. When these genes become disabled by mutation, they can no longer act against tumors, leading to a much greater chance of developing breast and ovarian cancers.

In the general population, about 1 in 400 women carry BRCA mutations, which most health experts feel is too rare to recommend the wide use of screening (which leads insurance companies to not cover the test). However, for Ashkenazi Jewish women, the risk is 10 times higher, leading to calls for increased screening in this population. The test itself is relatively simple, checking for three specific mutations and costing less than $200.

"We found that women who knew they were BRCA-positive and chose to keep their breasts were much more likely to be diagnosed with noninvasive breast cancer, earlier-stage invasive breast cancer, and need less morbid cancer therapy; but most importantly their survival was better," Rabinovitch noted, suggesting that results argue for routine BRCA screening in women of Ashkenazi Jewish descent.

"However even among those of us who did the study, we do not agree on when is the best age for genetic screening," she added. "My colleagues who live in Israel suggest it should be done at age 30 (the age at which significant cancer risk begins), but I think that's too late."

The reason has to do with the ability to screen embryos for BRCA mutations and to choose to implant only the embryos without BRCA mutation.

"Testing at age 30 is useful for the woman—it's before she is likely to develop breast or ovarian cancer and so offers her the opportunity for surgical prevention or increased cancer screening. However, by that age, many women have made the decision to get pregnant, and you've deprived them of the option to undergo procedures which would prevent passing on the BRCA mutation to their children. While not all women will choose this, I think they should be given the opportunity to do so," Rabinovitch said.

Another challenge with early BRCA testing is the social stigma in some communities that can be associated with a positive finding. "When do you share with a partner your BRCA status? Would this impact a partner's interest in marriage or having children? These legitimate and important questions are among the consequences of genetic testing," she explained.

Overall, Rabinovitch advises Ashkenazi Jewish women (and men) to be screened for the BRCA mutation "if they are willing to deal with the consequences of that information." If not, Rabinovitch points out, "it can result in a whole lot of anxiety without much benefit."

Study results add to a growing body of evidence that Rabinovitch hopes will eventually be used to guide new BRCA screening recommendations in the U.S. and Israel for healthy Ashkenazi Jews and other high-risk populations.

Tuesday, July 9, 2019

Researchers Discover New Genetic Link to Premenopausal Breast Cancer

​University of Alberta researchers have added a new genetic marker to the breast cancer map, helping to expand the list of genetic mutations clinicians can watch for in cancer screenings.

The genetic marker—called rs1429142—was found to confer a higher risk of breast cancer in Caucasian women carrying the genetic variation compared to women without the variation. In premenopausal women, that risk reached as high as 40 percent. The ability to identify those genes and their variants can be vital to early detection and life-saving treatment.

"This is important because the more we are able to create a complete picture of all the genes and all the variations and mutations that contribute to breast cancer, the closer we get to developing a genetic screen for breast cancer on a population level," said Sambasivarao Damaraju, PhD, Professor at the University of Alberta Department of Laboratory Medicine & Pathology and a member of the Cancer Research Institute of Northern Alberta. "If we can identify women at risk before they are diagnosed, and as long as we have the resources to mitigate that risk through preventative approaches, we can reduce the overall burden of breast cancer risk in a population."

Though the study primarily focused on genetic causes of breast cancer in Caucasian women, Damaraju's team went on to validate their findings in women of Chinese and African descent to explore the impact demographics may have on cancer risk.

"One of the real benefits of this research is that it brings a lot of focus to premenopausal breast cancer, which otherwise wasn't thought much about," said Mahalakshmi Kumaran, MTech, Damaraju's graduate student and first author on the paper.

Research Details

The study, published in the International Journal of Cancer, is the first of its kind to examine breast cancer risk in Caucasian women divided into premenopausal and postmenopausal groupings (2019; https://doi.org/10.1002/ijc.32407). Because the majority of breast cancers are diagnosed in women over the age of 55, most genetic association studies focus on postmenopausal women. However, inherited forms of cancers, typically related to genetic mutations, are more likely to be more aggressive and be diagnosed earlier in life.

The researchers examined more than 9,000 women from Alberta for the study, utilizing samples from patients diagnosed with breast cancer and unaffected healthy controls from the Alberta Cancer Research Biobank and the Alberta's Tomorrow Project, respectively.

The DNA isolated from the participants' blood provided clues to specific chromosomes that showed links to breast cancer risk. Using those clues, the team began to zero in on the specific regions of the chromosome to locate genetic variations across samples. They noticed that rs1429142 showed a consistent association with breast cancer risk in multiple tests. When the data was analyzed based on menopausal status, the risk was shown to be significantly higher for premenopausal women.

After confirming the link between the genetic variant and breast cancer, the team then took the extra step of zooming in on the genomic region to identify the specific location of the gene on the chromosome and marking it for future researchers.

"Finding this genetic marker is like starting with a high-resolution Google map of the world, and then slowly zooming in to the image of your house," Damaraju said. "It is valuable to do because now we have essentially planted a road sign on the chromosome that can help future researchers to carry out further in-depth studies."

Using international data from other genetic studies of breast cancer, and contributions from Vanderbilt University and St. Jude Children's Research Hospital investigators from Tennessee, the team was also able to validate their findings in women of Chinese and African descent. They found that women of African descent were at a particularly high risk of premenopausal breast cancer as a result of the variant gene. This underlined the idea that genetic ancestry plays an important role in cancer risk.

While the study focused primarily on the genetic variation present on a single chromosome, Damaraju said they also found promising leads for identifying more cancer-related genetic markers on other chromosomes as well. In the future, he hopes to see his research contribute to a more precise method of treating breast cancer by tailoring therapies to the specific needs of the patient.

"My focus for the last 20 years has been to build a pipeline from genetic research to benefit the patient," he said. "We identify the genetic predispositions and focus on developing population-related risk models to enable potential screening of populations and eventually possible interventions."

Monday, July 8, 2019

Clinical Safety, Efficacy of IMG-7289 in Myelofibrosis & Link to AML

AMSTERDAM—Positive safety and early efficacy clinical data regarding the lysine-specific demethylase (LSD1) inhibitor, IMG-7289, were presented at the 24th Congress of the European Hematology Association. Based on the findings, research has expanded to a phase IIb trial and the evaluations of clinical investigations in additional myeloid diseases. The data, from the ongoing IMG-7289-CTP-102 phase I/IIa clinical trial, showed that IMG-7289 was well-tolerated in patients with high or intermediate-2 risk myelofibrosis resistant to or intolerant of approved therapy. In addition, the therapy was effective in reducing spleen volumes and substantially improved symptom scores in a majority of evaluable patients. The expanded phase IIb study, expected to enroll 35 additional patients, will utilize a modified dosing schedule of IMG-7289 that safely optimizes efficacy. Additional trial sites have been added in the U.S., EU, and U.K. (see clinicaltrials.gov NCT03136185).

The data presented is from a cohort of 16 enrolled patients, 15 of whom had received one or more prior treatments including ruxolitinib. All patients began treatment with a sub-therapeutic dose of 0.25 mg per kg, with doses increasing until platelet count rested between 50 and 100K/μL. Twelve patients (75%) sustained a platelet count within this target zone at a dose of 0.81 mg/kg, with 14 patients (88%) completing the 85-day study. Nine patients were evaluable for efficacy, with six (66%) showing a reduction of spleen volume via imaging and five (56%) recording a greater than 50 percent reduction in total symptom score and two (22%) recording an improved bone marrow fibrosis score at 12 weeks.

The study has not shown safety signals, dose-limiting toxicities, or patient deaths with a median duration of treatment at 156 days. Fourteen patients in the study reported a total of 239 adverse events.

"LSD-1 inhibition has shown positive preclinical potential for treating myelofibrosis. This first report of clinical data suggesting that IMG-7289 is safe and tolerable in patients is cause for optimism in this terrible disease," said Kristen Pettit, MD, Assistant Professor of Medicine at the University of Michigan and a principle investigator of the study. "Even with a conservative dosing approach to evaluate safety, we saw encouraging improvements in patients' symptoms and spleen sizes. Continued evaluation of this therapeutic candidate under the modified clinical trial design with a more aggressive dosing approach will be a critical next step."

Monday, July 8, 2019

T-Cell Immunotherapy Prevents Relapse in Small Leukemia Trial

​By Jake Siegel

The statistics are grim: For patients with high-risk acute myeloid leukemia, more than 60 percent will relapse within 2 years of a bone marrow transplant. The return of their cancer is the leading cause of death for these patients.

But results from a small trial of genetically modified immune cells hint at a way of protecting these patients. Scientists at Fred Hutchinson Cancer Research Center used engineered T cells to prevent relapse in 12 acute myeloid leukemia (AML) patients after a bone marrow transplant put their disease in remission. They all remain cancer-free after a median follow-up of more than 3 years.

Those findings contrast with outcomes in a cohort of similar patients who received transplants around the same time but did not receive engineered T cells. In this comparison group of 88 patients, 46 percent relapsed.

The trial was small and non-randomized, noted Aude Chapuis, MD, one of the study's leaders, and it was limited to very sick patients. But the researchers are encouraged by the results.

"These patients don't have any options when it comes to preventing relapse, but here we feel we have a signal," Chapuis said. "We're very excited to pursue it further."

The trial described in the Nature Medicine paper grew out of Fred Hutch's trailblazing research into a particular type of adoptive T-cell therapy (2019;25:1064–1072). Phil Greenberg, MD, one of the study's leaders and the head of Fred Hutch's Program in Immunology, initially developed the approach. It involves refining the receptors on a T cell to target cancer-specific molecules.

For this trial, the T cells were engineered to home in on a protein called WT1, which is far more common on leukemia cells than on healthy ones. The team first published results of its WT1 research in 2013. Back then, the scientists observed that the engineered T cells could directly target and kill some leukemia cells.

But they also observed significant variation in how sensitive the modified T-cell receptors were to WT1. That sparked a hunt for a T-cell receptor with an exceptionally strong affinity for the protein. The researchers screened cells from many healthy donors before finding one receptor that was especially "sticky" for WT1. Using the sticky receptor as a blueprint, the team could insert genetic instructions for it into other T cells, enabling them to make this anti-WT1 receptor.

Billions of these engineered T cells were given to each of the 12 AML patients on the trial. More than 3 years later, the researchers could still detect T cells in these patients that expressed the genetically modified receptor—suggesting this type of treatment could provide long-lasting protection against the return of cancer, Chapuis noted.

The study also offers a proof-of-principle that scientists could expand the number of targets for engineered T-cell therapies, she explained. The approach of creating an optimal T-cell receptor could extend cell therapy to many more types of cancers. "Successfully going after WT1 opens the door to more targets for immunotherapy."

The researchers said that the particular T-cell receptor technology used in this trial won't be developed further for patient use. But as they've been doing for years, Chapuis, Greenberg, and Fred Hutch colleagues will continue to refine and improve their approach based on what they've learned in the hopes of bringing immunotherapy to more patients. They're already working in the lab on the next iterations, which aim to make these treatments more effective and longer-lasting.

"We've learned a lot through this trial," Chapuis said. "Our 2.0 will be better as we go from bench to bedside and back again."

Jake Siegel is a staff writer at Fred Hutchinson Cancer Research Center.