TAG: "Cancer"

Unnecessary chemo? Many women don’t know risk of breast cancer recurrence

UCLA-led study finds that Latino women are twice as likely to have unnecessary treatment.

By Venetia Lai, UCLA

Although 90 percent of women with early-stage breast cancer said they were aware they took a genomic test that identified their level of risk for a recurrence of the disease, 1 in 5 didn’t know the results of that analysis, according to a new fact sheet by the UCLA Center for Health Policy Research.

The test, called gene expression profiling, or GEP, is used by physicians to help guide treatment decisions and can potentially help people avoid unnecessary chemotherapy. One of a number of emerging “precision medicine” genomic technologies, the GEP estimates the activity of specific genes in breast cancer cells, which can help predict whether there is a greater chance for breast cancer to return. Those with a high risk for cancer growth benefit by having chemotherapy as part of their treatment, the authors write, but chemo has no added value for those with a low risk.

The report is based on a national study of nearly 900 women younger than 65 who were diagnosed with early stage estrogen-receptor–positive, lymph-node–negative breast cancer. The Center for Health Policy Research collaborated with researchers from Harvard University’s Brigham and Women’s Hospital and Aetna.

The study also found that 15 percent of Hispanic women with a low risk for recurrence of breast cancer had unnecessary chemotherapy as part of their treatment, more than double the rate for the group as a whole (7 percent).

“No one should have to go through the stress and discomfort of chemo without understanding the personal risks and benefits,” said Ninez Ponce, the center’s associate director and senior author of the study. “At the very least, patients should know their options. Right now, some women may be making treatment decisions based on incomplete information.”

Although 9 in 10 women surveyed said they were aware that they had taken a test that would determine their risk profile, the percentage who knew about the test varied significantly by racial and ethnic group. Only 78 percent of Hispanic women and 85 percent of African-American women were aware of the test, compared with 94 percent of white women and 98 percent of Asian-American women.

Additionally, approximately 20 percent of those surveyed said they still did not know whether the test result indicated a high or low risk for recurrence of cancer — a significant information gap. Nearly 10 percent of Hispanics and 6 percent of African Americans said their doctors did not discuss the test or test results with them, compared with just 3 percent of whites and 2 percent of Asian Americans.

Among the high-risk patients, all of the Hispanic and Asian-American women and 81 percent of African-American and white women had chemotherapy, according to the report.

One in eight women will be diagnosed with breast cancer in her lifetime. The authors write that women who know they have a low risk for recurrence have the opportunity to avoid overtreatment and the side effects of chemotherapy, which include fatigue, hair loss, nausea, vomiting, diarrhea, bruising and bleeding.

The research was funded by Aetna.

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Ovarian cancer-specific markers set stage for early diagnosis

Some mRNA isoforms identified in study also could act as new therapeutic targets.

By Heather Buschman, UC San Diego

Ovarian cancer is notoriously difficult to diagnose and treat, making it an especially fatal disease. Researchers at the UC San Diego School of Medicine and Moores Cancer Center have now identified six mRNA isoforms (bits of genetic material) produced by ovarian cancer cells but not normal cells, opening up the possibility that they could be used to diagnose early-stage ovarian cancer. What’s more, several of the mRNA isoforms code for unique proteins that could be targeted with new therapeutics. The study is published the week of May 25 by the Proceedings of the National Academy of Sciences.

“We were inspired by many studies aimed at using DNA to detect cancer,” said first author Christian Barrett, Ph.D., bioinformatics expert and project scientist in the UC San Diego School of Medicine Institute for Genomic Medicine. “But we wondered if we could instead develop an ovarian cancer detection test based on tumor-specific mRNA that has disseminated from cancer cells to the cervix and can be collected during a routine Pap test.”

While DNA carries all the instructions necessary for life, its actual sequence contains much more than just the genes that code for proteins. In contrast, mRNAs are complementary copies of just the genes. They carry the recipe for every protein that the cell will produce from the nucleus to the cytoplasm, where cellular machinery can read the recipe and build the corresponding proteins. According to the authors of this study, the advantage of using cancer mRNA for diagnosis rather than DNA is sheer number — a cancer cell might harbor just one or a few copies of a DNA mutation, but mRNA variants can occur in hundreds to thousands of copies per cell.

To determine if mRNAs can be used to distinguish ovarian cancer cells from normal cells, the team developed a custom bioinformatics algorithm and used it to mine two large public databases of genetic information — The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) program, both sponsored by the National Institutes of Health. TCGA is a catalog of RNA and DNA from 500 tumors covering many cancer types, while GTEx is a database of RNA and DNA from normal tissue samples. From these, the researchers were able to analyze mRNA sequence data from 296 ovarian cancers and 1,839 normal tissue samples.

Using this bioinformatics approach, the researchers identified six mRNA isoform molecules that have the tumor specificity required for an early detection diagnostic of ovarian cancer. They also validated their digital results in the real world using RT-quantitative PCR, a gene amplifying technique, to detect the same ovarian cancer-specific mRNA molecules in lab-grown cells.

Beyond their diagnostic potential, some of the mRNA isoforms identified in this study could also act as new therapeutic targets. These mRNA isoforms are predicted to encode proteins with unique amino acid sequences, which might allow them to be specifically targeted with certain therapeutics, such as monoclonal antibodies or T-cell-based vaccines. What’s more, the ovarian cancer-specific mRNA isoforms themselves could also be targeted with new therapeutic drugs.

“Our experimental findings were made in a laboratory and were performed on ovarian cancer cells from cell lines,” said study co-author Cheryl Saenz, M.D., a clinical professor of reproductive medicine who specializes in treating gynecologic cancers. “Clinical trials will need to be conducted on women to confirm the presence of these markers in women that we know have cancer, as well as to document the absence of the markers in women that do not have ovarian cancer.”

The authors acknowledge a few limitations to their approach, including technical limitations in detecting mRNA isoforms, a shortage of normal ovarian and fallopian tube control samples and the possibility that tumor cells that disseminate to the cervix may not genetically act the same as the primary tumor.

Still, based on these promising initial results, the authors recommend expanding their process for identifying tumor-specific mRNA isoforms to the 30 additional tumor types for which sufficient amounts of RNA sequence already exist.

Iris and Matthew Strauss, San Diego-based philanthropists who helped fund the study, are also excited by the promise this finding holds. “We created the Iris and Matthew Strauss Center for Early Detection of Ovarian Cancer in memory of our daughter, Stefanie Dawn Strauss,” said Iris Lynn Strauss. “To further honor our daughter, we provided support for this study in an effort to help other women obtain early detection from this dreadful and deadly disease.”

Additional co-authors of this study include Christopher DeBoever, Kristen Jepsen, Dennis A. Carson, and Kelly A. Frazer, all of UC San Diego.

This research was also funded, in part, by the National Cancer Institute (grant P30CA023100) and Colleen’s Dream Foundation.

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Community effort provides new ‘gold standard’ for genomic data analysis

Comprehensive assessment of methods for identifying mutations in cancer genomes.

Josh Stuart, UC Santa Cruz

By Tim Stephens, UC Santa Cruz

A coalition of leaders in the cancer genomics research community has published the first findings from a project to develop robust methods for detecting cancer mutations. The results, published today (May 18) in Nature Methods, provide an important new benchmark for researchers, helping to define the most accurate methods for identifying somatic mutations in cancer genomes. The study could be the first step in creating a new global standard to determine how well cancer mutations are detected.

Co-author Josh Stuart, professor of biomolecular engineering at UC Santa Cruz, helped organize the ICGC-TCGA-DREAM Somatic Mutation Calling Challenge, which merged the efforts of the world’s largest cancer genome sequencing consortia — the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) — with those of Sage Bionetworks and the DREAM project (Dialogue on Reverse Engineering Assessment and Methods). Other project leaders include cancer researchers at the Ontario Institute for Cancer Research (OICR) and Oregon Health & and Science University (OHSU).

“We owe it to cancer patients to interpret tumor DNA information as accurately as we can. This study represents yet another great example of harnessing the power of the open, blinded competition to take a huge step forward in fulfilling that vision,” said Stuart, a lead TCGA representative on the project. “We still have important work ahead of us, but accurate mutation calls will give a solid foundation to build from.”

Tumor genomes

The SMC Challenge, which was initiated in November 2013, was an open call to the research community to address the need for accurate methods to identify cancer-associated mutations from whole-genome sequencing data. Although genomic sequencing of tumor genomes is exploding, the mutations identified in a given genome can differ by up to 50 percent just based on how the data is analyzed.

Research teams were asked to analyze three in silico (computer simulated) tumor samples and publicly share their methods. The 248 separate analyses were contributed by teams around the world and then analyzed and compared by challenge organizers. When combined, the analyses provide a new ensemble algorithm that outperforms any single algorithm used in genomic data analysis to date.

The authors of the paper also report a computational method, BAMSurgeon (developed by co-lead author Adam Ewing at UC Santa Cruz), capable of producing an accurate simulation of a tumor genome. In contrast to tumor genomes from real tissue samples, the challenge organizers had complete knowledge of all mutations within the simulated tumor genomes, allowing comprehensive assessment of the mistakes made by all submitted methods, as well as their accuracy in identifying the known mutations.

Dramatic differences

The submitted methods displayed dramatic differences in accuracy, with many achieving less than 80 percent accuracy and some methods achieving above 90 percent. Perhaps more surprisingly, 25 percent of teams were able to improve their performance by at least 20 percent just by optimizing the parameters on their existing algorithms. This suggests that differences in how existing approaches are applied are critically important — perhaps more so than the choice of the method itself.

The group also demonstrated that false positives (mutations that were predicted but didn’t actually exist) were not randomly distributed in the genome but instead they were in very specific locations, and, importantly, the errors actually closely resemble mutation patterns previously believed to represent real biological signals.

“Overall these findings demonstrated that the best way to analyze a human genome is to use a pool of multiple algorithms,” said co-lead author Kathleen Houlahan, a junior bioinformatician at OICR working with the challenge lead, Dr. Paul Boutros. “There is a lot of value to be gained in working together. People around the world are already using the tools we’ve created. These are just the first findings from the challenge, so there are many more discoveries to share with the research community as we work through the data and analyze the results.”

Team sport

“Science is now a team sport. As a research community we’re all on the same team against a common opponent,” said Dr. Adam Margolin, director of computational biology at OHSU and co-organizer of the challenge. “The only way we’ll win is to tackle the biggest, most challenging problems as a global community, and rapidly identify and build on the best innovations that arise from anywhere. All of the top innovators participated in this challenge, and by working together for a year, I believe we’ve advanced our state of knowledge far beyond the sum of our isolated efforts.”

Dr. Stephen Friend, president of Sage Bionetworks, said the goal is “no longer one of winning the challenge but instead of constantly addressing an ever-changing horizon. And given the complex heterogeneity of cancer genomes and the rapid rate with which next-generation sequencing technologies keep changing and evolving, this seems like an ideal approach to accelerate progress for the entire field.”

In addition to Ewing and Stuart, UCSC co-authors of the paper include David Haussler, professor of biomolecular engineering and director of the UC Santa Cruz Genomics Institute, and Kyle Ellrott, a software developer at the institute.

DREAM challenges pose fundamental questions about systems biology and translational medicine. Designed and run by a community of researchers from a variety of organizations, DREAM challenges invite participants to propose solutions — fostering collaboration and building communities in the process.

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Women with dense breasts may not need more screening

Study shows importance of assessing cancer risk when evaluating for additional screening.

By Elizabeth Fernandez, UC San Francisco

As the debate continues to swirl around the medical significance of dense breasts and whether extra screening should be done, a new study led by UC San Francisco has found that women with dense breasts may need only routine mammograms unless they are at high risk.

In their paper, the researchers said that five-year breast cancer risk is a critical component, and breast density should not be the sole factor in deciding whether supplemental screening is justified because not all women with dense breasts are at high risk of cancer.

Research has shown that women with dense breasts may be more likely to develop cancer.

The study was published today (May 18) in Annals of Internal Medicine.

The research focused on approximately 365,000 women ages 40 to 74 years old who had undergone a regular digital screening mammogram and had no history of breast implants or breast cancer.

Breast density is determined only by mammograms – having dense breasts makes it more difficult for X-rays to pass through the breast tissue and can mask tumors. Breasts are considered dense if the woman has a lot of fibrous or glandular tissue but not much fatty tissue, according to the American Cancer Society.

“Not all women with dense breasts have a high enough risk of cancer to justify supplemental screening,” said lead author, Karla Kerlikowske, M.D., a professor of medicine and epidemiology and biostatistics at UCSF and a primary care physician at the UCSF-affiliated San Francisco VA Medical Center. “We found that for the vast majority of women undergoing mammography – including those with dense breasts but low five-year breast cancer risk – the chance of developing breast cancer within 12 months of a normal mammogram was low. Women with extremely dense breasts and intermediate to high five-year breast cancer or heterogeneously dense breasts and high five-year breast cancer risk were at highest risk for developing breast cancer after a normal mammogram.”

“Our findings can help guide women and providers in discussing supplemental imaging and whether to consider extra testing,” said Kerlikowske. “This study provides a starting point to identify women who may have the most to gain from supplemental imaging or alternative imaging strategies.”

Currently, 22 states require that women be notified if they have dense breasts. The laws also encourage women to discuss supplemental screening with their medical providers. Similar legislation, which would set a minimum standard for notification and recommend that women discuss with their doctors whether further screening is necessary, is pending in Congress, which would have a considerable impact nationally, affecting tens of millions of women annually.

Digital mammography, used by the vast majority of mammography facilities, detects 81 to 87 percent of breast cancers among women 40 to 79 years old, reported the authors. But its ability to detect breast cancer in women with extremely dense breasts is lower.

As a result, supplemental imaging has been suggested for women with dense breasts to heighten their chances for tumor detection before women become symptomatic. While supplemental imaging for women with dense breasts can increase cancer detection, it also can lead to more false-positive results and more unnecessary biopsies.

In the prospective cohort study drawing upon statistics from 2002 to 2011, the researchers analyzed screening data collected by the Breast Cancer Surveillance Consortium (BCSC). Overall, nearly half the women in the study had dense breasts, and the proportion with heightened five-year risk was highest among those with extremely dense breasts.

“We found that rather than using only breast density to decide whether women with dense breasts should be considered for supplemental imaging, breast cancer risk should be taken into consideration,” said Kerlikowske, a member of the breast oncology program at the UCSF Helen Diller Family Comprehensive Cancer Center. “The BCSC risk calculator that includes age, family history of breast cancer, history of breast biopsy, breast density and race can be used to calculate five-year breast cancer risk. Determining breast cancer risk along with knowing a woman’s breast density will optimize the identification of women with high interval cancer rates who may benefit from supplemental screening.”

The authors noted that they were unable to assess the benefits of patient discussions with providers about supplemental breast imaging.

Co-authors are Weiwei Zhu, M.S., a biostatistician at the Group Health Cooperative in Seattle and the University of Washington School of Medicine; Anna N.A. Tosteson, Sc.D., a professor of medicine at The Dartmouth Institute; Brian L. Sprague, Ph.D., an assistant professor of surgery at the University of Vermont Cancer Center; Jeffrey A. Tice, M.D., a UCSF associate professor of medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center; Constance D. Lehman, M.D., Ph.D., a professor at the University of Washington School of Medicine and vice chair of radiology; and  Diana L. Miglioretti, Ph.D., a professor of biostatistics at UC Davis and co-leader of the Breast Cancer Surveillance Consortium.

The research was supported by the National Cancer Institute-funded Breast Cancer Surveillance Consortium (P01 CA154292, HHSN261201100031C and U54 CA163303). The collection of cancer data used in the study was supported in part by several state public health departments and cancer registries in the U.S.

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Study explains how early childhood vaccination reduces leukemia risk

Chronic infections push ‘pre-leukemia’ cells, common in newborns, into malignancy.

By Juliana Bunim, UC San Francisco

A team led by UC San Francisco researchers has discovered how a commonly administered vaccine protects against acute lymphoblastic leukemia (ALL), the most common type of childhood cancer.

The Haemophilus influenzae Type b (Hib) vaccine not only prevents ear infections and meningitis caused by the Hib bacterium, but also protects against ALL, which accounts for approximately 25 percent of cancer diagnoses among children younger than 15 years, according to the National Cancer Society. The Hib vaccine is part of the standard vaccination schedule recommended by the Centers for Disease Control and is routinely given to children in four doses before 15 months of age.

Though the cancer protection offered by the Hib vaccine has been well established in epidemiological studies, it is not well-known among the public at large, and the mechanism underlying this effect has been poorly understood. Now, in work to be reported on today (May 18) in Nature Immunology, an international team led by UCSF researchers has shown that recurrent Hib infections can put certain immune-system genes into overdrive, converting “pre-leukemia” blood cells — which are present in a surprisingly large number of newborns — into full-blown cancer.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said Markus Müschen, M.D., Ph.D., professor of laboratory medicine at UCSF and senior author of the study. “Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Many newborns carry oncogenes — genes that could potentially cause cancer — in their blood cells, but only 1 in 10,000 will eventually develop ALL. In the new study, the researchers tested the idea that chronic inflammation caused by recurrent infections might cause “collateral damage” — additional genetic lesions — in blood cells already carrying an oncogene,  promoting their transformation to overt disease.

Led by co-first authors Srividya Swaminathan, Ph.D., a former UCSF postdoctoral fellow now at Stanford University School of Medicine, and Lars Klemm, assistant research specialist at UCSF, the research team conducted experiments with mice that homed in on two enzymes known as AID and RAG as the drivers of this process.

AID and RAG introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response. But in the presence of chronic infection, the group found, AID and RAG are strongly hyperactivated, and they cut and mutate genes randomly, including important gatekeepers against cancer.

By studying genetically engineered pre-leukemia cells lacking either AID or RAG, as well as cells lacking both enzymes, the team found that AID and RAG working together is critical to introduce the additional lesions that result in life-threatening disease.

Though the researchers focused on Hib, a bacterial infection, they believe that the same mechanisms may be at work in viral infections. The team is currently conducting experiments to determine if protection against leukemia is also provided by vaccines against viral infections, such as the well known MMR vaccine at the center of recent anti-vaccination controversies.

Mel F. Greaves, M.D., Ph.D., professor of cell biology at the Institute of Cancer Research, in London, is among the scientists who developed the theory that chronic and recurrent immune reactions during infancy promote cancer in children and one of the co-authors of the study. “The study provides mechanistic support for the hypothesis that infection or inflammation promotes the evolution of childhood leukemia and that the timing of common infections in early life is critical,” said Greaves.

Also participating in the research were scientists from the University of Freiburg; Cambridge University; the Wellcome Trust Sanger Institute; the University of Southern California; Heinrich-Heine-Universität Düsseldorf; the University of Ulm; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Yale School of Medicine.

The work was funded by the National Institutes of Health; the National Cancer Institute; the Leukemia and Lymphoma Society; the William Lawrence and Blanche Hughes Foundation; the California Institute for Regenerative Medicine; the Wellcome Trust; and Cancer Research UK.

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Specific genetic mutation may increase risk for breast cancer

Study shows women with KRAS-variant also likelier to develop new cases of breast cancer.

Joanne Weidhaas, UCLA

By Reggie Kumar, UCLA

UCLA researchers have discovered that for women with a relatively common inherited genetic mutation, known as the KRAS-variant, an abrupt lowering of estrogen in the body may increase the risk for breast cancer and impact the biology of their breast cancer. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer, independent of a first breast cancer.

The two-year study, led by Dr. Joanne Weidhaas, a professor of radiation oncology at the UCLA Jonsson Comprehensive Cancer Center and director of translational research at the David Geffen School of Medicine, analyzed data from more than 1,700 women with breast cancer who submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.

Weidhaas’ team found that acute estrogen withdrawal, as experienced after removal of the ovaries or when hormone replacement therapy was discontinued, and/or a low estrogen state were associated with breast cancer in women with the KRAS-variant. Acute estrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study. In addition, up to 45 percent of breast cancer patients with the KRAS-variant eventually developed a second independent breast cancer — representing a 12-fold greater risk than women with breast cancer who did not have the KRAS-variant.

“Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation,” Weidhaas said. “This study’s findings, showing that estrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers.”

The findings are contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, but the study is in agreement with follow-up studies which found that estrogen alone might actually protect women from breast cancer.

“The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing estrogen, or at a minimum, at least tapering it appropriately,” Weidhaas said. “We hope that there are real opportunities to personalize risk-reducing strategies for these women, through further defining the most protective estrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman’s first breast cancer diagnosis.”

The study was published in the journal Cell Cycle.

The research, which was supported by the National Cancer Institute, was done in collaboration with MiraKind, a nonprofit organization.

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Revealing kidney cancer’s secret

Tumors gain survival advantage by reprogramming their metabolism.

Robert Weiss, UC Davis

By Dorsey Griffith, UC Davis

An international team of scientists, led by UC Davis nephrologist Robert Weiss, have used a sophisticated combination of proteomics and metabolomics to show how renal cell carcinoma (RCC) reprograms its metabolism and evades the immune system. In addition, the study found that cancer grade has a major impact on this reprogramming. These results, published in the journal Cancer Research, point to new therapeutic options for this particularly deadly cancer.

“The mortality for someone with highly metastatic RCC is somewhere in the 90 percent range,” said Weiss, professor of nephrology and internal medicine at UC Davis and chief of nephrology at the VA Northern California Health System in Sacramento. “We now know this cancer is actually reprogramming its environment to minimize the immune response.”

The team used a unique approach to make these discoveries, combining proteomics with metabolomics. The proteomic analyses examined how RCC affects levels of different proteins. Meanwhile, metabolomic studies performed a similar task with metabolites­ – the compounds that remain when larger molecules are broken down or metabolized.

Both proteomic and metabolomic analyses are quite intensive, requiring major computational and statistical firepower. However, combining these two “omics” provided a better view of the mechanisms that govern kidney cancer, like using a wide-angle lens to capture a complete landscape.

“One particular omics technique will tell you part of the story, but it won’t give you the whole thing,” said Weiss, a scientific member of the UC Davis Comprehensive Cancer Center. “We wanted to combine metabolomics and proteomics and come up with a ‘unified field theory’ to look at the metabolites in cancer.”

This more comprehensive approach paid dividends in several ways. For example, the proteomic analysis showed how RCC increases an enzyme that breaks down the amino acid tryptophan. In turn, the metabolomics studies flagged that tryptophan metabolites suppress the immune system.

A similar story unfolded with glutamine, another amino acid. By manipulating glutamine, kidney cancer removes reactive oxygen species, a key immune system weapon that would usually help destroy the cancer.

“Normally, immune surveillance would shut down the cancer, but RCC has evolved to turn off the immune system, giving it a survival advantage,” said Weiss.

The research also uncovered another important story: how cancer grade affects this remodeling. While cancer stage describes how far the disease has progressed through the body – from localized to metastasized – grade describes how abnormal the cancer cells have become. In the case of RCC, higher-grade cancers were remodeling their environments more aggressively.

“We often treat kidney cancers the same, regardless of grade,” noted Weiss. “We should think about grade, and not just stage, when we’re treating patients.”

From a procedural standpoint, the study highlights how combining proteomics and metabolomics can detect cancer mechanisms that either method, by itself, might miss. In addition, this better understanding of how cancer grade affects its ability to alter its surroundings could help oncologists develop more personalize therapies.

But even more importantly, the work points to new therapeutic targets, such as the tryptophan and glutamine pathways, which could help clinicians unleash the immune system against RCC.

“We are going to be testing inhibitors against some of these enzymes so we can stop the tumors from creating these immunosuppressant metabolites,” said Weiss.

Other researchers were Hiromi Wettersten, Josephine Trott and Omran Abu Aboud Dexter Morin at UC Davis; A. Ari Hakimi and James  Hsieh at Memorial Sloan Kettering Cancer Center; Cristina Bianchi and Roberto Perego at the University of Milano-Bicocca; Megan. Johnstone and Dallas Donohoe at the University of Tennessee; Steven Stirdivant, Bruce Neri and Robert Wolfert at Metabolon; and Benjamin Stewart at Lawrence Livermore National Laboratory.

This research was funded by National Institutes of Health grants 5UO1CA86402, 1R01CA135401-01A1 and 1R01DK082690-01A1, the Medical Service of the U.S. Department of Veterans’ Affairs, the LLNL-UCDCC Fitzpatrick Award, and grants from the Paula Moss Trust and the J. Randall & Kathleen L. MacDonald Research Fund in Honor of Louis V. Gerstner.

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20th annual Taste for a Cure raises $1M for UCLA

Event honored David Madden of Fox Broadcasting Co.

The chefs of Taste for a Cure (from left): Tommaso Tarantino, Tanino Drago, Piero Selvaggio, Salvatore Marino, Giacomino Drago, Vittorio Lucariello and Steve Samson.

By Peter Bracke, UCLA

UCLA’s Jonsson Cancer Center Foundation held its 20th annual Taste for a Cure fundraiser to benefit UCLA’s Jonsson Comprehensive Cancer Center on May 1 at the Beverly Wilshire Hotel in Los Angeles. The event raised over $1 million — a record for Taste for a Cure.

The event honored David Madden, president of entertainment at Fox Broadcasting Co. with the 2015 Gil Nickel Humanitarian Award. The award was named in memory of JCCF supporter Gil Nickel, proprietor of Napa Valley’s Far Niente, Nickel and Nickel and Dolce wineries, who lost his battle with melanoma in 2003. Dinner committee co-chairs included CAA’s Joe Cohen, the Holman Group’s Jon Holman, Far Niente Winery’s Larry Maguire, UTA’s Jay Sures and Fox TV Group co-chairs Gary Newman and Dana Walden.

“We are incredibly proud of Taste for a Cure’s legacy and the tangible strides we’ve made in cancer research over the past 20 years,” said Dr. Judith Gasson, director of the Jonsson Comprehensive Cancer Center. “As we celebrate two decades of groundbreaking scientific advances, we also are thrilled to recognize David Madden. Madden has long been acknowledged for his talent and leadership in the entertainment business, but at Taste for a Cure we honor him for his dedication to our community. I am proud that our industry partners have been so keen to get involved in this important cause and I want to thank David and the co-chairs for their tireless commitment that makes this special event possible.”

The gifts are part of the Centennial Campaign for UCLA, a $4.2 billon fundraising drive scheduled to conclude in 2019, the university’s 100th anniversary.

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New combination treatment strategy to ‘checkmate’ brain tumors

Three different classes of anti-cancer drugs work synergistically against brain tumors.

Normal cell dividing (left) and stressed cancer cell dividing (right). PLK1 inhibitors stress cancer cells, making them easier to kill.

By Heather Buschman, UC San Diego

Therapies that specifically target mutations in a person’s cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers at the UC San Diego School of Medicine and Moores Cancer Center identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer.

The study, published May 5 by Oncotarget, demonstrates that a mouse model of glioblastoma and human glioblastoma tissue removed from patients and cultured in the lab can be effectively treated by combining three classes of anti-cancer drugs: a drug that targets a cancer mutation in the Epidermal Growth Factor Receptor (EGFR) gene, a drug that increases stress in cancer cells and a drug that damages cancer cell DNA.

“Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move,” said senior author Clark Chen, M.D., Ph.D., associate professor of neurosurgery and vice chair of research and academic development at UC San Diego.

In up to 50 percent of glioblastomas, mutations in the EGFR gene render cancer cells insensitive to growth regulation by environmental cues, allowing them to grow uncontrollably. Yet highly specific EGFR inhibitors are not particularly effective against glioblastomas with EGFR mutations.

“When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR,” said Chen. “Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate.”

To develop such a strategy, Chen and his group turned to PLK1, a protein that regulates stress levels within glioblastoma cells and is essential for their survival. Chen and his group found that glioblastoma cells that developed resistance to EGFR inhibitors remain universally dependent on this protein.

In mouse models of glioblastoma and in explants of human glioblastoma, singular treatment with an EGFR inhibitor, a PLK1 inhibitor or the current standard of care drug (a DNA-damaging agent), each temporarily halted glioblastoma growth. But, like the human disease, the tumor eventually grew back. However, no detectable tumor recurrence was observed when a combination of all three classes of drugs was administered. The treated mice tolerated this combination regimen without showing significant side effects.

“It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer,” said study co-author Bob S. Carter, M.D., Ph.D., chief of neurosurgery at UC San Diego. “Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity.”

The three drugs administered to mice in this study were: BI2536, a PLK1 inhibitor; Gefitnib, an EGFR inhibitor; and TMZ, the standard-of-care chemotherapy for glioblastoma. The study authors note that while the safety or side effects of treating human patients will all three drugs is unknown, all are individually well-tolerated in humans. The clinical safety profiles of Gefitinib and TMZ are well-established for glioblastoma patients and PLK1 inhibitors have so far been well-tolerated in clinical trials (one has advanced to phase three clinical trials for acute myeloid leukemia).

Co-authors of this study include Ying Shen, UC San Diego and Shanghai Jiao Tong University; Jie Li, Diahnn Futalan, Tyler Steed, Jeffrey M Treiber, and Zack Taich, UC San Diego; Masayuki Nitta, Dana-Farber Cancer Institute; Deanna Stevens, Jill Wykosky, Frank B. Furnari, Webster K. Cavenee, and Arshad Desai, UC San Diego and Ludwig Cancer Research; Hong-Zhuan Chen, Shanghai Jiao Tong University; Oren J. Becher, Duke University Medical Center; Richard Kennedy, Queen’s University of Belfast; Fumiko Esashi, University of Oxford; and Jann N. Sarkaria, Mayo Clinic.

This research was funded, in part, by the Sontag Foundation, Burroughs Wellcome Foundation, Kimmel Foundation, Doris Duke Foundation and Forbeck Foundation.

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Surgery for terminal cancer patients still common

Surgeons increasingly selective in deciding whether to operate.

By Dorsey Griffith, UC Davis

The number of surgeries performed on terminally ill cancer patients has not dropped in recent years­, despite more attention to the importance of less invasive care for these patients to relieve symptoms and improve quality of life. But new research from UC Davis also finds that the morbidity and mortality among patients with terminal cancer has declined because surgeons are selecting to operate on healthier patients.

The study, “Current Perioperative Outcomes for Patients with Disseminated Care Undergoing Surgery” was published online this week in the Journal of Surgical Research.

“Surgeons are becoming wiser,” said study lead author Sarah Bateni, a UC Davis resident surgeon. “Our research suggests that surgeons may be operating on healthier patients who are more likely to recover well from an operation. These are patients who can perform activities of daily living without assistance, for example.”

Bateni’s interest in the appropriate surgical care of people with late-stage cancer grew from observing terminally ill patients whose acute problems were addressed through surgery, and who then suffered complications resulting in lengthy stays in intensive care units, and even in death.

“It is common that patients end up dying in the intensive care unit instead of being managed with medication with hopes of returning home with their families, including with hospice care,” she said.

For the study, Bateni used the American College of Surgeons National Surgical Quality Improvement Program between 2006 and 2010 to identify 21,755 patients with stage IV cancer, meaning that the disease had metastasized, or spread, beyond the primary tumor site.

Over the five years in the study period, surgical interventions declined just slightly, from 1.9 percent to 1.6 percent of all procedures. The most frequent operations were surgeries to alleviate bowel obstructions among cancer patients with metastatic disease.

Also over time, the patients undergoing surgery were more independent and fewer had experienced dramatic weight loss or sepsis, a serious blood infection. These characteristics are generally associated with poorer surgical outcomes.

The patients’ rate of morbidity, a measure of illness, significantly decreased, from 33.7 percent in 2006 to 26.6 percent in 2010. Mortality declined as well, although more modestly, from 10. 4 percent to 9.3 percent over the study period.

Why surgeons continue to operate on patients at such high risk for complications and death is due to several factors, Bateni said.

“Some of it has to do with the patients and families,” she said. “If the patient is uncomfortable, the family wants a solution. In some cases, the surgeon also may be too optimistic about what the surgical outcome will be.”

What Bateni also found was that just 3 percent of the patients with terminal cancer had Do Not Resuscitate (DNR) directives in place at the time of their surgery. DNRs, part of advanced directives used in end-of-life planning, direct physicians to withhold advanced life support if the patient stops breathing or their heart stops beating.

Bateni said the study results imply that patients, families and care providers, including surgeons, are often delaying discussions about the goals of the care and the priorities at the end of life.

She cautioned that delaying end-of-life discussions can have serious consequences because it can lead to delayed referrals for palliative care and hospice. In addition, the patient risks undergoing multiple invasive, uncomfortable procedures in an attempt to prolong life, despite being against the patient’s goals of care and how they wish to spend their final days of life.

“It’s really important that the doctor has an end-of-life, goals-of-care discussion prior to the time that the patient comes into the hospital with an acute illness,” she said. ”Patients should be referred to a palliative care counselor or  have a comprehensive end-of-life discussion to ensure that their goals are respected as soon as they are diagnosed with cancer, especially those with cancers that have a high mortality rate.”

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Patients with gastrointestinal tumors at higher risk of other cancers

UC San Diego findings may have clinical implications.

By Yadira Galindo, UC San Diego

Researchers at UC San Diego School of Medicine conducted the first population-based study that characterizes the association and temporal relationship between gastrointestinal stromal tumors (GIST) and other cancers. The results, published by Cancer on April 30, indicate that 1 in 5.8 patients with GIST will develop additional malignancies before and after their diagnosis.

Specifically, patients with GIST are more likely to develop other sarcomas, non-Hodgkin’s lymphoma, carcinoid tumors, melanoma, colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate and renal cell cancers.

“Only 5 percent of patients with gastrointestinal stromal tumors have a hereditary disorder that predisposes them to develop multiple benign and malignant tumors,” said Jason K. Sicklick, M.D., assistant professor of surgery and UC San Diego Moores Cancer Center surgical oncologist. “The research indicates that these patients may develop cancers outside of these syndromes, but the exact mechanisms are not yet known.”

The researchers said further studies are needed to understand the connection between GIST and other cancers, but the findings may have clinical implications.

“Patients diagnosed with gastrointestinal stromal tumors may warrant consideration for additional screenings based on the other cancers that they are most susceptible to contract,” said co-author James D. Murphy, M.D., assistant professor of radiation oncology and UC San Diego Moores Cancer Center radiation oncologist.

When compared to the United States population, the researchers found that people with GIST had a 44 percent increased prevalence of cancers occurring before a GIST diagnosis and a 66 percent higher risk of developing cancers after diagnosis. The most common tumors were those of the genitourinary tract, breast, respiratory and blood.

Non-Hispanic patients had a higher incidence of other cancers before a GIST diagnosis. Patients whose tumors were smaller than 10 centimeters had a higher probability of a second cancer than patients whose growth was larger. People with tumors smaller than 2 cm had the greatest likelihood of developing additional malignancies, both before and after diagnosis.

Co-authors include Grace L. Ma, Joel M. Baumgartner, Lisa Madlensky, Adam M. Burgoyne, Chih-Min Tang and Maria Elena Martinez, all at UC San Diego Moores Cancer Center.

Funding for this research came, in part, from the National Institutes of Health (KL2 RR031978 and K08 CA168999), the GIST Research Fund and a UC San Diego Academic Senate Health Sciences Research Grant.

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Pancreatic cancer risk linked to weak sunlight

UC San Diego epidemiologists suggest harm may come from low vitamin D.

By Scott LaFee, UC San Diego

Writing in the April 30 online issue of the Journal of Steroid Biochemistry and Molecular Biology, researchers at the UC San Diego School of Medicine report pancreatic cancer rates are highest in countries with the least amount of sunlight. Low sunlight levels were due to a combination of heavy cloud cover and high latitude.

“If you’re living at a high latitude or in a place with a lot of heavy cloud cover, you can’t make vitamin D most of the year, which results in a higher-than-normal risk of getting pancreatic cancer,” said first author Cedric F. Garland, Dr.P.H., adjunct professor in the Department of Family Medicine and Public Health and member of UC San Diego Moores Cancer Center.

“People who live in sunny countries near the equator have only one-sixth of the age-adjusted incidence rate of pancreatic cancer as those who live far from it. The importance of sunlight deficiency strongly suggests – but does not prove – that vitamin D deficiency may contribute to risk of pancreatic cancer.”

Limited foods naturally contain vitamin D. Fatty fish, such as salmon and tuna, are good sources; beef liver, cheese and egg yolks provide small amounts. Vitamin D is often added as a fortifying nutrient to milk, cereals and juices, but experts say most people also require additional vitamin D to be produce by the body when skin is directly exposed to sunlight. Specifically, ultraviolet B radiation. Skin exposed to sunshine indoors through a window will not produce vitamin D. Cloudy skies, shade and dark-colored skin also reduce vitamin D production.

The UC San Diego team, led by Garland and Edward D. Gorham, Ph.D., associate professor, had previously shown that sufficient levels of a metabolite of vitamin D in the serum, known as 25-hydroxyvitamin D was associated with substantially lower risk of breast and colorectal cancer. The current paper is the first to implicate vitamin D deficiency with pancreatic cancer.

Researchers studied data from 107 countries, taking into account international differences and possible confounders, such as alcohol consumption, obesity and smoking. “While these other factors also contribute to risk, the strong inverse association with cloud-cover adjusted sunlight persisted even after they were accounted for,” said Garland.

UC San Diego researchers had previously identified an association of high latitude with a higher risk of pancreatic cancer. Garland said the new study advances that finding by showing that an estimate of solar ultraviolet B that has been adjusted for heavy cloud cover produces an even stronger prediction of risk of pancreatic cancer.

Pancreatic cancer is the 12th most common cancer in the world, according to World Cancer Research Fund International, with 338,000 new cases diagnosed annually. Incidence rates are highest in North America and Europe; lowest in Africa and Asia. It is the seventh most common cause of death from cancer.

Coauthors of the study include Raphael E. Cuomo, Kenneth Zeng and Sharif B. Mohr, all at UC San Diego.

Funding for this research came, in part, from UC San Diego Department of Family Medicine and Public Health.

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