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Yale Cancer Center research highlighted at 2017 SABCS

December 07, 2017

Yale Cancer Center (YCC) researchers attended the 40th annual San Antonio Breast Cancer Symposium (SABCS), from December 5-9, and bringing news of major advances against a disease that strikes more than 250,000 women and men in the United States each year.

The Symposium is a five-day program attended by an international audience of academic and private researchers and physicians from over 90 countries.

Some of the research highlights presented by YCC scientists at the symposium included:

Immune system is more active in primary breast cancer than in metastatic disease New immunotherapies that unleash the body’s own defenses against tumors are showing high promise in early-stage breast cancer, especially when combined with chemotherapies, but these drugs have seen less success in metastatic disease. “These differing results may be because the immune system is weakened in the metastatic environment,” said Lajos Pusztai, M.D., DPhil, chief of Breast Medical Oncology and co-director of the Genomics, Genetics, and Epigenetics Program at YCC. Pusztai reported at this year’s SABCS on a study examining signs of immune activity in primary and metastatic breast cancer tissues. The researchers examined pairs of primary and metastatic tumors from two cohorts of patients, with one cohort of 45 women providing matched tissues. They discovered that metastatic samples displayed significantly lower counts of infiltrating immune cells (a sign of active immune action) than primary tumor samples. The immune cells in metastatic tissue also showed fewer signs of activity. Surprisingly, the PD-L1 immune checkpoint protein, which helps tumors evade the immune system, was also lower in metastases, suggesting that other immunosuppressive mechanisms are prominent in metastases.

“We found major differences in the immune microenvironments of primary tumors and metastatic tumors,” Pusztai summed up. “Metastatic tumors are much more immune-inert, which may explain our limited success in treating metastatic breast cancer.” On the upside, analyzing the expression of 730 immune-related genes, the scientists identified several mechanisms that cancer cells use to evade the immune system, which provide opportunities to target these mechanisms and restore anti-tumor immunity.

“Based on these observations, we can design clinical trials with rational combinations of immunotherapies for metastatic cancer,” Pusztai said.

Exploring one explanation for why trastuzumab fails some with HER2-positive breast cancer Trastuzumab is one of the great success stories of breast cancer in the past two decades, successfully treating millions of women whose tumors express the HER2 protein. But for many women, the cancer comes back. Back in 2015, a team led by David L. Rimm, M.D., Ph.D., director of Pathology Tissue Services at YCC and Yale School of Medicine, presented one explanation as to why trastuzumab might fail. Part of the HER2 protein is inside the cell (the “intracellular domain”) and part is outside the cell (the “extracellular domain”). Trastuzumab attaches to the extracellular domain, but sometimes that domain gets scissored off. “We discovered that patients who have that region of HER2 cut off don’t benefit so much from trastuzumab,” Rimm said. At SABCS this year, Rimm reported new supporting evidence for this explanation gathered from a study of 60 patients with HER2-positive breast cancer. This work employed a new approach called imaging mass cytometry, which uses mass spectrometry to precisely measure levels of many proteins. The study confirmed that decreased extracellular domain was associated with worse response to trastuzumab, and also found that cancer-killing T cells were present at a higher frequency when the extracellular domain was present, suggesting that trastuzumab may be helped by the immune system when it kills tumor cells.

In a separate study also presented at the conference, Rimm and his colleagues reported on an analysis with conventional quantitative fluorescence based on the NeoALTTO clinical trial for women with early-stage HER2-positive breast cancer. NeoALTTO compared results from treatment before surgery with trastuzumab or lapatinib or both. The Yale investigation among 382 women participating in NeoALTTO found that those whose tumors had lower levels of the HER2 extracellular domain part benefitted less from trastuzumab. But the same group of women also appeared to do better when lapatinib, which targets the intracellular domain, was added to trastuzumab.

“Our research is working toward two goals for women with HER2-positive breast cancer,” Rimm said. “One is to determine who needs another drug with their trastuzumab to make sure they don't recur. The second goal is to figure who doesn't need trastuzumab, since we know that some of the patients who get trastuzumab don't benefit.”

Tracking gene silencing to assess breast cancer risk How can we do a better job predicting a woman’s risk of developing breast cancer? One approach is to examine how actively genes are expressed in healthy breast tissue. Erin Hofstatter, M.D., co-director of the Cancer Genetics & Prevention Program at YCC and Smilow Cancer Hospital, reported progress in this quest by a study presented at SABCS 2017 comparing how gene expression is silenced in a process known as DNA methylation in healthy breast tissue, both from women who have developed cancer and those who haven’t. In DNA methylation, groups of methyl (a hydrocarbon molecule) attach to genes and silence their expression. “It’s normal to have some methylation on genes, and the more methyl groups you stick on a gene, the more it will be quieted,” said Hofstatter. In previous work looking at healthy breast tissue in women with or without breast cancer, “we saw that the women who had concurrent breast cancer appeared to have a differential DNA methylation pattern in their normal tissue compared to healthy unaffected women.”

Her team’s latest work studied DNA methylation in 93 samples of normal breast tissue, 40 from women with breast cancer (mostly estrogen-positive) and 53 from women without. The researchers found about 200 loci (positions on the genes) where methylation was significantly different on normal tissue from women who had developed cancer compared to those who hadn’t. Most of these loci were located in genes that are enriched in two molecular pathways, one for cell adhesion and the other (curiously enough) involved primarily in nerve-cell signaling.

The next step in her research, Hofstatter said, will be to analyze these samples to see how DNA methylation evolves over time, and how it correlates with breast cancer risk. The work is part of her effort to find better measures of breast cancer risk, similar to the role that blood pressure and cholesterol play in cardiovascular health. Such tests will help women who are at heightened genetic risk or have family histories of breast cancer to better assess their options when considering preventive medications or surgery.

About Yale Cancer Center Yale Cancer Center (YCC) is one of only 49 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in southern New England. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.

Submitted by Renee Gaudette on December 08, 2017