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Thursday, January 12, 2017

Breast cancer screening in Denmark was associated with a substantial increase in the incidence of nonadvanced tumors and DCIS but not with a reduction in the incidence of advanced tumors. The rate of overdiagnosis was also substantial, according to findings of a cohort study recently published in Annals of Internal Medicine (doi: 10.7326/M16-0270).

Effective breast cancer screening should detect early-stage cancer and prevent advanced disease. Overdiagnosis occurs when mammography detects small tumors that may never affect the patient's health during a lifetime. The problem with overdiagnosis is that it exposes patients to the potential harms of treatment, such as surgery, chemotherapy, and radiation, without a clinical benefit. Whether screening reduces the incidence of advanced tumors has important treatment implications.

"Effective breast cancer screening should reduce the incidence of advanced tumors," study authors wrote. "Screening mammography detects many small tumors that would not have become clinically evident in the remaining lifetime without screening (overdiagnosis). Whether screening reduces the incidence of advanced tumors has important therapeutic implications. Overdiagnosed lesions may be unnecessarily treated with surgery, chemotherapy, and radiation, which subjects women to the harms of therapy without benefit."

Using data from two comprehensive Danish cancer registries, researchers sought to examine the association of screening with a reduction in the incidence of advanced cancer and estimate the level of overdiagnosis in the country's breast screening program, which offered biennial mammography for women aged 50 - 69 years beginning in different regions at different times.

Women in Denmark who lived in areas covered by Danish breast cancer screening programs from 1991 to 2010 were compared with those who lived in areas of Denmark that did not offer mammography screening.

The authors measured the incidence of advanced (>20mm) and nonadvanced (<20 mm) breast cancer tumors in screened and unscreened women. To examine trends in overdiagnosis, the authors compared the incidence of advanced tumors in women aged 50 to 84 in screening and nonscreening areas and compared the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in both screening and nonscreening areas.

They concluded that screening was not associated with lower incidence of advanced tumors and approximately 1 in 3 invasive tumors and cases of DCIS diagnosed in screened women represent overdiagnosis.

In an accompanying editorial, Otis Brawley, MD, MACP, Chief Medical Officer of the American Cancer Society said that it's time to accept that overdiagnosis is real and that the benefits of breast screening have been overstated (doi: 10.7326/M16-2850). He writes that "considering all small breast cancer lesions to be deadly aggressive cancer is the "pathology equivalent of racial profiling."

This does not mean that screening should be abandoned, but we should try to recognize its limitations, use it in the most effective way possible, and try to improve it.

"We must carefully examine screening, realize its limitations, maximize its effectiveness, and try to improve it," Brawley wrote. "In addition, we must examine all elements of breast cancer control (to include prevention) and evaluate how they are best used."

Brawley suggests that more emphasis should be focused on preventing breast cancer through diet, weight control, and exercise.

Thursday, January 5, 2017

The American Association for Cancer Research (AACR) announced the first public release of cancer genomic data aggregated through its initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE). The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at eight international institutions, making it among the largest fully public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including data on nearly 3,000 patients with lung cancer, more than 2,000 patients with breast cancer, and more than 2,000 patients with colorectal cancer. The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR website.

"We are excited to make publicly available this very large set of clinical-grade, next-generation sequencing data obtained during routine patient care," said Charles L. Sawyers, MD, FAACR, AACR Project GENIE Steering Committee Chairperson, Chairperson of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, and a Howard Hughes Medical Institute investigator. "These data were generated as part of routine patient care and without AACR Project GENIE they would likely never have been shared with the global cancer research community. We are committed to sharing not only the real-world data within the AACR Project GENIE registry but also our best practices, from tips about assembling an international consortium to the best variant analysis pipeline, because only by working together will information flow freely and patients benefit rapidly."

The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA). They are derived from patients whose tumors were genetically sequenced as part of their care at one of the eight international institutions that participated in the first phase of AACR Project GENIE. Therefore, the genomic data are clinical grade, which means they are the highest quality possible.

By releasing the data to the global cancer research community, the consortium aims to catalyze new clinical research that will accelerate the pace of progress against cancer. There are many ways in which the data can be exploited to benefit patients in the future, including through the following: the validation of gene signatures of drug response or prognosis; the ability to identify new patient populations for drugs previously approved by the FDA; the expansion of patient populations that will benefit from existing drugs; and the identification of new drug targets and biomarkers.

"I am extremely proud that the American Association for Cancer Research, as the Coordinating Center for AACR Project GENIE, is delivering on its promise to make these important data publicly available just over a year after unveiling the initiative," said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. "I would like to thank like to thank Dr. Sawyers for his vision in conceptualizing this exciting project and also the eight international institutions that have contributed these valuable data to AACR Project GENIE. By actively collaborating to create this extensive, freely available data set, they are leading a revolution in cancer genomics research that holds the promise for significantly enhancing the future utility of precision medicine in the treatment of cancer and for the benefit of patients around the world."

The eight institutions participating in AACR Project GENIE phase 1 are:

  • Dana-Farber Cancer Institute, Boston, Mass.;
  • Gustave Roussy Cancer Campus, Paris-Villejuif, France;
  • The Netherlands Cancer Institute, Amsterdam, on behalf of the Center for Personalized Cancer Treatment, Utrecht, The Netherlands;
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Md.;
  • Memorial Sloan Kettering Cancer Center, New York, N.Y.;
  • Princess Margaret Cancer Centre, Toronto, Ontario, Canada;
  • University of Texas MD Anderson Cancer Center, Houston, Texas; and,
  • Vanderbilt-Ingram Cancer Center, Nashville, Tenn.​

To expand the AACR Project GENIE registry, the consortium is now accepting applications for new participating centers, which is a year sooner than originally anticipated. Any nonprofit institution that meets certain criteria should submit an application to become a project participant.

Tuesday, January 3, 2017

​​An enzyme that plays an active role in inflammation could be a natural way to suppress tumors and ulcers in the colon that are found in colitis associated cancer (CAC), a type of colorectal cancer that is driven by chronic inflammation, according to a new study.

Researchers at Georgia State University and Stony Brook University have identified the tumor suppressor role of matrix-metalloproteinase (MMP9), which belongs to a family of enzymes called proteinases and serves as an essential regulator of extracellular matrix components via a novel mechanistic pathway. The findings are reported in the journal Oncotarget (doi: 10.18632/oncotarget.13406).

"In the setting of chronic inflammation, MMP9 expression functions as a silver lining by suppressing the advancement of the tumor microenvironment in CAC," said Pallavi Garg, PhD, Assistant Professor in the Institute for Biomedical Sciences at Georgia State.

Inflammation can be a beneficial response to tissue damage or pathogens, but if unregulated it can become chronic inflammation and induce malignant cells in tissue that lead to cancer. Patients with chronically active ulcerative colitis have a significantly higher risk (up to 50% depending on the group of subjects) of developing CAC. The risk of CAC increases with the duration of the disease and the severity of inflammation.

The protein expression and activity of MMP9 is undetectable in most healthy adult tissues, including the colon and intestine, but it is highly expressed in a variety of inflammatory states. Previous studies have shown that MMP9 derived from epithelial cells plays a protective role in the development of CAC. Almost 80 percent of cancers have epithelial cell origin. This study aimed to determine whether epithelial-derived MMP9 has a defensive role of tumor suppressor in CAC and the underlying molecular mechanism.

Researchers used transgenic mice that expressed MMP9 in the colonic epithelium for in vivo experiments. In vitro experiments used human colon carcinoma cells with and without MMP9 and mouse embryonic fibroblasts, which are connective tissue cells that make the extracellular matrix and collagen and play an important role in tissue repair.

The researchers found mice that expressed MMP9 in the epithelium exhibited fewer tumors and increased apoptosis, or programmed cell death that gets rid of cells that are no longer needed or are a threat to the organism. Human colon carcinoma cells that overexpressed MMP9 showed decreased cell proliferation, less DNA damage and cell cycle arrest in the S-phase to prevent cell proliferation.

In addition, they found that epithelial-derived MMP9 suppresses tumors in CAC by activating the MMP9-Notch1-ARF-p53 axis pathway, which increases apoptosis, initiates cell cycle arrest and keeps a check on DNA damage.

Wednesday, December 21, 2016

Serum levels of ANGPT2, a protein related to angiogenesis, was found to predict response to and influence the outcomes of treatment with immune checkpoint inhibitors in patients with advanced melanoma, according to a study published in Cancer Immunology Research (doi: 10.1158/2326-6066.CIR-16-0206).

The study found that ANGPT2 may also serve as a target for combination therapies of inhibitors of immune checkpoint and angiogenesis.

"In this study, we found ANGPT2 to be a predictive and prognostic biomarker of response to the inhibitors of immune checkpoints CTLA-4 and PD-1," said F. Stephen Hodi, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute, Professor of Medicine and investigator at the Ludwig Center at Harvard Medical School in Boston. "We found additional evidence suggesting a role for angiogenic factors in immune regulation and the possibility of targeting the immune system and angiogenic factors with combinations in the treatment of cancer."

Specific aspects of tumor cells, immune cells, and other components of the tumor microenvironment contribute to the complexity of the biology of cancer, which make identifying tissue biomarkers that can predict response to immune checkpoint inhibitors a huge challenge, Hodi explained. One way to tackle this is by identifying serum biomarkers that can be measured and monitored with ease.

In this study, Hodi and colleagues studied the role of the angiogenic factor ANGPT2 in immune regulation and its potential role as a biomarker for immune checkpoint inhibitors. ANGPT2 is a regulator of blood vessel maturation and enables angiogenesis. In prior studies, this protein was associated with resistance to treatment with bevacizumab (Avastin), an antibody therapeutic that targets another angiogenesis factor, VEGF.

The investigators studied serum samples collected before and within 3 months of treatment initiation from 48, 43, and 43 patients with advanced melanoma treated with the anti-CTLA-4 antibody ipilimumab (Yervoy), ipilimumab plus bevacizumab, and an anti-PD1 therapeutic (nivolumab [Opdivo] or pembrolizumab [Keytruda]), respectively. Patients were from three different clinical trials in which survival data were available.

About 17, 20, and 37 percent of the patients in the three studies had complete or partial responses, and the median follow-up time for all of them combined was 33 months.

The researchers found that among patients treated with ipilimumab alone, the median overall survival (OS) in those with high versus low levels of pretreatment serum ANGPT2 was 12.2 months and 28.2 months, respectively. In those treated with ipilimumab plus bevacizumab, the median OS was 10.9 months versus 19.3 months.

In patients treated with an anti-PD1, the median OS was 7.3 months among those with high pretreatment ANGPT2; median OS had not yet been reached in those from the low-group as more than half of the patients were alive at the time of this report.

In order to understand how changes in serum ANGPT2 levels with treatment influenced clinical outcomes, the researchers computed the fold change of the protein levels before and during treatment and found that in patients who received ipilimumab alone, those with ANGPT2 levels below and above the fold-change cutoff of 1.25 had OS of 12.4 months and 28.1 months, respectively. They made similar observations in patients from the ipilimumab plus bevacizumab study, but the difference was not statistically significant.

All patients in these two studies whose ANGPT2 levels increased by at least 25 percent either had stable or progressive disease, except for one patient who had a partial response.

When the investigators combined the data from patients in the three groups, those with high pretreatment ANGPT2 levels and large fold changes had the worst survival, and those with low pretreatment protein levels and small fold changes had the best survival. Patients with high pretreatment ANGPT2 levels and small fold changes and those with low pretreatment ANGPT2 levels and large fold changes had intermediate survival. This correlation between the dynamic ANGPT2 levels and survival consolidates the role of this protein as a prognostic biomarker.

In order to understand the mechanism by which ANGPT2 influences clinical outcomes, the investigators conducted laboratory-based tests using a specific subset of macrophages that are present in the tumor microenvironment and found that ANGPT2 increased the expression of PD-L1 on these cells. PD-L1 is a protein that plays a role in immune suppression, and some immune checkpoint inhibitors target the PD-1/PD-L1 axis.

"These in vitro studies suggested that angiogenic factors not only play a role in blood vessel formation in tumors but also have immune-regulatory effects; therefore, therapeutics that inhibit angiogenesis could synergize with immune checkpoint blockade," Hodi said. "We would, however, like to confirm the findings from this study in a larger patient population in the future."

The investigators are conducting a phase I trial testing a combination of tremelimumab and an ANGPT2 antibody in patients with advanced melanoma.

Tuesday, December 20, 2016

The first data on rare sarcomas in Asian patients was recently presented in three studies at the ESMO Asia 2016 Congress in Singapore.

Just half of patients with advanced angiosarcoma received chemotherapy even though it improved overall survival. CIC-rearranged sarcomas are shown to have a much worse prognosis than BCOR-rearranged sarcomas and clinical features are identified to aid accurate diagnoses.

Angiosarcoma is the focus of two studies conducted by the newly formed Asian Sarcoma Consortium (ASC) (Abstract 501O_PR, Abstract 502O_PR). Treatment is challenging since the disease tends to be infiltrative, making surgery with clear margins difficult, while radiation is a poor option for tumors on the scalp and face. Chemotherapy has demonstrated activity in angiosarcoma but long-term remission is rare.

Both studies retrospectively included patients attending eight sites in six countries during 1990 to 2016. The first study outlines the epidemiology, real-world treatment, and clinical outcomes of angiosarcoma in Asia. The median age of the 423 patients was 67 years, about 60 percent had cutaneous angiosarcoma (they were more likely to be older, male, and have localized disease), while 40 percent had visceral angiosarcoma.

In the localized setting, only about 60 percent of patients underwent surgery, but this was significantly lower in the cutaneous (55%) than visceral (75%) cohort. In those who underwent surgery, negative margins were only achieved in approximately 70 percent of cases. Close to half of patients who underwent surgery relapsed. Median relapse free survival was just 12.3 months with no statistical difference between the cutaneous (12.9 months) versus visceral (9.5 months) groups. Patients were more likely to relapse if they were more than 65 years old or had positive surgical margins.

In the advanced setting, only about half of patients received chemotherapy. Median overall survival was 9.5 months with no significant difference between cutaneous (11.5 months) and visceral (8.3 months) groups. ECOG (Eastern Cooperative Oncology Group) performance status was an independent predictor of survival. However, after adjusting for ECOG performance status, overall survival was significantly better in patients who received chemotherapy than those who did not.

"This is one of the largest studies in angiosarcoma and we found that overall prognosis was poor," said lead author Richard Quek, MD, Deputy Head and Senior Consultant, National Cancer Centre Singapore. "In patients with localized disease, negative surgical margin was prognostic for relapse free survival yet it was only achieved in 70 percent of patients. Neoadjuvant (pre-operative) treatment, be it chemotherapy or radiation, might enhance resectability of these tumors and thereby improve survival outcomes.

"In patients with advanced disease we demonstrated that, after adjusting for ECOG performance status, chemotherapy was associated with improved overall survival. But only half of our patients actually received chemotherapy, hence it would be important to understand the reasons behind this low treatment rate," Quek continued. "Could these be physician-related factors? And if so, is more sarcoma-related continuing medical education needed to enhance care for our patients?"

The second angiosarcoma study outlined the clinical characteristics and treatment of 277 patients with advanced metastatic or unresectable disease. The median age was 64 years. The predictors of better prognosis were younger age, female sex, and cutaneous (rather than visceral) disease. Use of chemotherapy gradually increased over the 20-year period, with a preference for paclitaxel and liposomal doxorubicin over other treatments. Progression-free survival in patients receiving at least one line of chemotherapy was 3.8 months. Overall survival was 8.3 months but was significantly higher in patients who received at least one line of palliative chemotherapy (11.5 months) than those who did not (4.4 months).

"It's the first time we have data on expected survival for Asian patients with advanced metastatic or unresectable angiosarcoma," said lead author Tom Chen, MD, Attending Physician, National Taiwan University Hospital, Taipei, Taiwan. "This data will help us to develop clinical trials and new treatments for Asian angiosarcoma patients."

The third study focused on Ewing sarcoma-like small round cell sarcomas (Abstract 503O_PR). Ewing sarcoma is molecularly characterized by a EWSR1 gene alteration or FUS rearrangement. Small round cell sarcomas without these molecular characteristics are designated "Ewing sarcoma-like" disease. Recent molecular genetic studies have identified CIC-rearranged sarcoma (CIC-DUX4, CIC-DUX4L, CIC-FOXO4) and BCOR-rearranged sarcoma (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR) among these Ewing sarcoma-like small round cell sarcomas. The recently presented study describes the clinical characteristics and treatment outcomes of these two sarcomas.

The study included 17 patients with CIC sarcoma, of whom 12 were male. Median age was 22 years, all cases were soft tissue tumors, and 59 percent of patients had local pain. The seven BCOR sarcoma patients were all male. Median age was 14 years and cases included bone and soft tissue tumors.

The 5-year overall survival rate was 28.2 percent for CIC sarcoma and 100 percent for BCOR sarcoma. Metastases were present in 71 percent of CIC patients at the initial visit and none of the BCOR patients. Only 29 percent of CIC patients responded to chemotherapy compared to 75 percent of BCOR patients.

"CIC-rearranged sarcomas have a much worse prognosis than BCOR-rearranged sarcomas," said lead author Makoto Endo, MD, PhD, Attending Physician, National Cancer Centre, Tokyo, Japan. "CIC and BCOR sarcomas were previously classified as the same tumor. Our research will help us to make a precise diagnosis and should improve the management of these patients."

Commenting on the studies, Thomas Brodowicz, MD, Program Director, Bone and Soft Tissue-Sarcoma Unit, Medical University Vienna, Austria, said: "The two studies on angiosarcoma show that immediate progression-free survival and overall survival are low, which reflects the aggressiveness of this disease. It would be useful to have a more detailed breakdown of the patients-- for example, the treatment and outcomes of primary angiosarcoma versus secondary, which forms at the site of radiation treatment for a previous cancer. It would also be helpful to know whether paclitaxel is more effective when taken every 3 weeks or weekly, which has an antiangiogenic effect that could be beneficial in angiosarcoma."

"The study by Dr. Endo provides practice-changing information," he concluded. "It shows that Ewing sarcoma-like small round cell sarcomas can be further categorized by their specific mutations, which have a strong prognostic impact. This should help us to tailor treatment."