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Friday, November 17, 2017

Mutational signature analysis found mismatch repair (MMR) deficient breast cancer tumors, which could potentially be targeted with PD-1 immune checkpoint inhibitors, according to a recent study (Can Res 2017; doi:10.1158/0008-5472.CAN-17-1083).

"Our research demonstrates the value of using mutation patterns to identify MMR deficiency in unselected breast cancer cases," said Serena Nik-Zainal, MD, PhD, Cancer Research UK (CRUK) Advanced Clinician Scientist and Honorary Consultant in Clinical Genetics at the University of Cambridge and Wellcome Trust Sanger Institute, Genome Research Limited in Cambridge, U.K. "These findings are important because a subset of patients may be responsive to immunotherapies such as PD-1 checkpoint blockade as has been demonstrated with MMR deficiency in colorectal and other cancers."

Cancers caused by MMR deficiency involve gene mutations that affect the ability of the cell to repair the mistakes that can happen during the DNA replication process, which the cells must perform each time they divide. MMR-deficient tumors have 10-100 times more mutations than tumors with intact MMR pathways.

Nik-Zainal and colleagues used previously published whole genome sequencing data of breast cancer tumors from 640 patients and analyzed mutational signatures. The also looked for mutations in multiple genes known to be associated with MMR deficiency: MLH1, MSH2, MSH6, PMS2, PMS1, SETD2, MYH11, EPCAM, TGFBR2, MLH3, and MUTYH, in order to identify the defects responsible for the MMR deficiency.

The researchers discovered 11 of 640 tumors harbored the MMR deficiency in variable amounts. "We found variations of mutations, including single base substitutions and small insertions/deletions," explained Nik-Zainal. In addition to base substitution mutational signatures specific to MMR deficient tumors, they also found an average of 20,870 small insertions/deletions in the 11 MMR-deficient breast cancer tumors compared to only a fraction, 270 on average, in the non-MMR-deficient tumors. "By looking at multiple signals, we identified a subset of tumors that would not have been detected as MMR-deficient using current clinical criteria for the assessment of breast cancer," she said.

Due to its high degree of sensitivity and specificity to classify tumors, mutational signature analysis might be a better biomarker for use in future clinical trials, according to Nik-Zainal. "In some recent pharmaceutical trials, the protocols used single biomarkers and startlingly different cutoff points to measure PD-L1 expression for tumor classification, which may explain the different results in progression-free survival outcomes," she explained. "With mutational signature analysis that investigates multiple mutations, we can see a direct readout of the pathway that has gone wrong. Our method might outperform the use of a single biomarker."

The main limitation of this study is that it is a technical analysis and the findings need to be tested in clinical trials. MMR deficiency is rare in breast cancer; the investigators found that only 1-2 percent of breast cancer tumors had MMR deficiency, Nik-Zainal noted. She added that, although this technology could be used to look for MMR deficiency in other cancers, assessing whether using these mutational signatures to tailor cancer treatment helps improve survival is important.


Friday, November 17, 2017

Seventy-two new genetic variants that contribute to the risk of developing breast cancer have been identified by a major international collaboration involving hundreds of researchers worldwide.

Of these variants, 65 are common variants that predispose to breast cancer and a further seven predispose specifically to estrogen-receptor negative breast cancer (Nature 2017; doi:10.1038/nature24284). The newly identified risk regions nearly double the number that are already known, thereby bringing the number of known common variants associated with breast cancer to around 180.

The findings are the result of work by the OncoArray Consortium, an endeavor involving 550 researchers from around 300 different institutions in six continents. In total, they analyzed genetic data from 275,000 women, of whom 146,000 had been diagnosed with breast cancer.

"These findings add significantly to our understanding of the inherited basis of breast cancer. As well as identifying new genetic variants, we have also confirmed many that we had previously suspected," said Doug Easton, PhD, Professor and Director of the Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, and one of the lead investigators on the study. "There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved."

By combining epidemiological data with other data from breast tissue, the researchers were able to make plausible predictions of the target genes in the large majority of cases. In addition, they showed for the first time that these genes are often the same as those that are altered in breast tumors.

Most of the variants were not found within genes, but rather within regions of the genome that regulate the activity of nearby genes. When the researchers looked at the pattern of these genetic regions, they discovered that this differed from that of those regions involved in predisposition to other common diseases.

"Given the size of these studies, we expected that we would find a lot of new breast cancer risk variants, but the studies tells us a lot more about which genes are involved, revealing many previously unsuspected genes and genetic mechanisms underlying breast carcinogenesis," noted Peter Kraft, PhD, Professor of Epidemiology at the Harvard TH Chan School of Public Health, Boston. "This should provide guidance for a lot of future research."

The studies identified genetic regions specifically associated with either oestrogen-receptor positive or oestrogen-receptor negative breast cancer, underscoring the fact that these are biologically distinct cancers that develop differently.

"These findings may inform improved risk prediction, both for the general population and BRCA1 mutation carriers," said Roger Milne, PhD, Associate Professor at Cancer Council Victoria in Melbourne. "A better understanding of the biological basis of oestrogen-receptor negative breast cancer may lead to more effective preventive interventions and treatments."

The risk variants identified in the two studies are common: while some are carried by one woman in a hundred, others are carried by more half of all women. Individually, the risks conferred by each variant are modest; however, because they are common and their effects multiply together, the combined effect is considerable. For example, the researchers estimated that 1 percent of women have a risk of breast cancer that is more than 3 times greater than the population at large. Larger differences in risk can be found if the genetic variants are combined with other hormonal and lifestyle factors that influence breast cancer risk.

The researchers believe these differences may be sufficient to change practice, such as in how women at different risks are screened. In many countries, women are offered screening by mammography from age 50; women at increased risk because of a family history can be offered screening earlier, and those at particularly high risk can be offered screening by MRI, which is more sensitive.

"Using data from genomic studies, combined with information on other known risk factors, will allow better breast cancer risk assessment, therefore helping to identify a small but meaningful proportion of women at high risk of breast cancer," said Jacques Simard, PhD, Professor at Université Laval, Quebec City, Canada.

"These women may benefit from more intensive screening, starting at a younger age, or using more sensitive screening techniques, allowing early detection and prevention of the disease," he concluded. "At the same time, this personalized information will also be useful to adapt screening modalities for women at substantially lower risk."


Friday, November 17, 2017

The presence of tumor-infiltrating lymphocytes (TILs) varied significantly in the tumors of African-American and European-American women with triple-negative breast cancer (TNBC), suggesting that TILs may be a useful prognostic biomarker, according to the results of a study presented at the Tenth AACR Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved this fall.

TNBC is a highly aggressive breast cancer subtype that afflicts African-American women at a higher rate than white women, and often involves a worse prognosis, said the study's lead author, Nikita Wright, BS, a PhD candidate at Georgia State University in Atlanta. TNBC does not express three of the proteins that cause other types of breast tumors to grow—estrogen receptor, progesterone receptor, or HER2/neu. Therefore, there are no targeted therapies currently available for TNBC.

Previous research has shown that African-American women tend to develop more aggressive subtypes of TNBC than European-American women, exacerbating the disparity in survival, Wright said.

"Thus, there is an urgent need to investigate robust, clinically applicable biomarkers that can help clinicians discern which patients are likely to have a more aggressive disease course and guide the personalized treatment of TNBC," she added.

Previous research has also shown that higher counts of TILs are associated with better survival in TNBC patients. Wright said further research would be required to explain the mechanisms, but one theory is that more aggressive tumors elicit stronger infiltration of lymphocytes into the tumor.

Study Methodology, Results

To compare the presence of TILs in African-American and European-American patients with TNBC, Wright and colleagues tested resection samples from 142 TNBC patients at Emory Hospital in Atlanta, and compared overall (stromal) TILs between patients of African-American and European-American descent. None of the patients had undergone neoadjuvant chemotherapy.

The results showed that African-American patients harbored significantly more overall TILs than European-American patients. Significant differences were also observed among early-stage TNBC patients, but not among late-stage patients.

The study also showed that high peripheral TILs were associated with better 10-year survival among early stage African-American TNBC patients, after adjusting for age, Nottingham grade, and stage.

A greater presence of overall and peripheral TILs were also associated with a lack of androgen receptor (AR) expression among early stage African-American TNBC patients. The lack of AR reception classifies some TNBC cases as quadruple-negative, and this subtype is more prevalent among African-American compared to European-American TNBC patients, Wright said.

Among African-American patients with early-stage TNBC, high TIL counts were also associated with younger age at diagnosis, increased intramammary lymph node involvement, and increased BRCA1-associated protein and PD-L1 expression, Wright said. Considering the range of characteristics that were associated with higher TIL counts, Wright said testing for TILs could potentially provide clinicians with useful information for TNBC patient prognosis.

"These findings uncover a previously unrecognized disparity in the tumor microenvironment between African-American and European-American TNBC patients," Wright said. "If confirmed, these findings suggest TILs can be used to predict patient prognosis in the early stages of disease for African-American TNBC patients. This insight is clinically actionable and of great potential value for guiding treatment of these patients so that their survival may be improved."

Wright said the study's main limitation is that it only included patients who did not receive neoadjuvant chemotherapy. She said retrospective studies that examine racial disparities in TILs among patients who did receive neoadjuvant chemotherapy could help confirm the role of TILs in TNBC.

Wednesday, November 15, 2017

Rare variants combined with background genetic risk factors may account for many unexplained cases of familial breast cancer, and knowing the specific genes involved could inform choice of prevention and treatment strategies, according to findings presented in a plenary session at the 2017 American Society of Human Genetics Annual Meeting in Orlando, Fla. (Abstract 293).

Researchers Na Li, MD, who presented the work; Ian Campbell, PhD, lead investigator; and their colleagues at the Peter MacCallum Cancer Centre in Melbourne, Australia, focused their study on patients at high risk of breast cancer: those with a personal or family history who were seeking an explanation.

"When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient," said Campbell. Unfortunately, in about half of these high-risk patients, no known genetic cause was found, suggesting a more complicated explanation. In such cases, cancer geneticists had long suspected that polygenic risk was involved.

Genes do not work on their own, but rather as part of one's overall genetic context, explained Li. "That 'polygenic risk' background is like a landscape full of hills and valleys, with each risky variant like a house on top of it," she said. "If you inherit a high-risk variant—a tall house—but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down."

The concept of background genetic risk is not new, but for many years, scientists did not have the tools to collect and analyze the thousands of genomes needed to quantify it. Recent improvements in next-generation sequencing technology have addressed this challenge. As a result, Li and colleagues were able to sequence up to 1,400 candidate breast cancer genes in 6,000 familial breast cancer patients and 6,000 cancer-free controls. In this large sample, they searched for potential cancer-associated genes suggested by the literature, collaborators, and their own previous results, and identified at least 46 genes that were at least twice as likely to have mutations among participants with breast cancer than in those without.

They also used the data to calculate a polygenic risk score for each patient, and combined this score with data on their high and moderate-risk variants to estimate each patient's overall risk of developing breast cancer. In the coming years, the researchers plan to expand the study internationally to further test and refine their findings across populations. They also hope to bring these more precise risk estimates into the clinic to more accurately reassure women about their personal risk of cancer, or—if risk is high—advise preventive strategies such as screening at a younger age.


Wednesday, November 15, 2017

In a newly published study, Cleveland Clinic researchers have uncovered differences in the bacterial composition of breast tissue of healthy women versus women with breast cancer. The research team has discovered for the first time that healthy breast tissue contains more of the bacterial species Methylobacterium, a finding which could offer a new perspective in the battle against breast cancer (Oncotarget 2017; doi:10.18632/oncotarget.21490).

Bacteria that live in the body influence many diseases. Most research has been done on the gut microbiome. Researchers have long suspected that a microbiome exists within breast tissue and plays a role in breast cancer, but it has not yet been characterized. The research team has taken the first step toward understanding the composition of the bacteria in breast cancer by uncovering distinct microbial differences in healthy and cancerous breast tissue.

"To my knowledge, this is the first study to examine both breast tissue and distant sites of the body for bacterial differences in breast cancer," said co-senior author Charis Eng, MD, PhD, Chair of Cleveland Clinic's Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare. "Our hope is to find a biomarker that would help us diagnose breast cancer quickly and easily. In our wildest dreams, we hope we can use microbiomics right before breast cancer forms and then prevent cancer with probiotics or antibiotics."

The study examined the tissues of 78 patients who underwent mastectomy for invasive carcinoma or elective cosmetic breast surgery. In addition, they examined oral rinse and urine to determine the bacterial composition of these distant sites in the body.

In addition to the Methylobacterium finding, the team discovered that cancer patients' urine samples had increased levels of gram-positive bacteria, including Staphylococcus and Actinomyces. Further studies are needed to determine the role these organisms may play in breast cancer.

"If we can target specific pro-cancer bacteria, we may be able to make the environment less hospitable to cancer and enhance existing treatments," stated co-senior author Stephen Grobmyer, MD, Section Head of Surgical Oncology and Director of the Breast Center at Cleveland Clinic. "Larger studies are needed, but this work is a solid first step in better understanding the significant role of bacterial imbalances in breast cancer."

The study provides proof-of-principle evidence to support further research into the creation and utilization of loaded nanoparticles, targeting these pro-cancer bacteria. Grobmyer and Eng are collaborating with investigators at Hebrew University, Jerusalem, Israel, to develop new treatments using nanotechnology to deliver antibiotics directly to the bacterial community in breast cancer.​