Cancer treatment as a double-edged sword

Even with today’s safer and more targeted anti-cancer drugs, scientists have been unable to satisfactorily explain the phenomenon of why treated cancers so often recur. The common theory is that the cancer cell develops “internal resistance to treatment,” and overrides the toxic effects of the drug.
Now, findings by a team of scientists led by Professor Yuval Shaked of the Technion-Israel Institute of Technology Faculty of Medicine and the Technion Integrated Cancer Center (TICC) could provide the key for reducing recurrence, and allowing anti-cancer drugs to do work as intended.

In their study published in The Journal of Pathology, the team shows that tumor relapse occurs when the body, in effect, mobilizes itself in favor of the tumor, causing recurrence of the disease, increasing its aggressiveness and creating metastases or tumor spread. Even selective, highly focused treatments that harm cancer cells almost exclusively lead to a similar response.

The administration of an anti-cancer drug is very aggressive intervention in the body,” explains Prof. Shaked. “Therefore, the body responds to chemotherapy the way it responds to trauma. This creates the effect of a double-edged sword: although chemotherapy kills cancer cells, it also causes the secretion of substances that confer resistance to the tumor. Even more selective treatments, with fewer side effects, cause physiological reactions that increase the aggressiveness of the disease.”

In this specific study, among other studies the group has published in this area, mice with multiple myeloma — a malignant disease of the plasma cells produced in bone marrow and spread throughout the body via the circulatory system — were treated with the selective anti-cancer drug Velcade (bortezomib). (Velcade is based on the discovery of ubiquitin, for which Professors Avram Hershko and Aaron Ciechanover of the Technion Faculty of Medicine won the Nobel Prize.)

The researchers found that treatment with Velcade led to a physiological reaction that actually reinforced the intensity of the myeloma in the mice. According to Prof. Shaked, the drug caused inflammatory cells (macrophages) in the bone marrow to enhance the aggressiveness of the disease and provide the cancer cells with resistance to treatment.

It is important to clarify that treatment with Velcade is essential and necessary,” says Prof. Shaked, “but its disadvantage is that along with the benefit there is damage.”

Next steps: inhibiting the mechanism that enhances the tumor

According to Prof. Shaked, “…understanding the mechanisms that enhance the tumor and accelerate the spread of metastases will enable us to develop methods to inhibit them.”

In fact, when the researchers inhibited the secreted factor related to the activity of inflammatory cells, they observed a decrease in the proliferation of cancer cells. Now they are working on various ways to inhibit the body’s response to anti-cancer treatments.

Ultimately we are talking about a trade-off between the intensity of the treatment and the intensity of the physical response. The moment the ratio is in favor of the treatment and to the detriment of the response, we will achieve effective treatment without a ‘fine’ in the form of enhanced metastasis. In addition, we can inhibit the body’s response using existing drugs, thereby enabling the anticancer drugs to get the job done.

Beyar-Katz, et al. Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy. The Journal of Pathology, 2016; 239 (3): 262 DOI: 10.1002/path.4723 [Abstract]

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Risk of undetected cancer in gynecologic surgery higher than previously thought

Minimally invasive gynecologic surgeries have advantages for patients, including shorter hospital stays, quicker recoveries, and less pain. However, power morcellation, a technique which cuts the uterus or fibroid into small pieces in order to extract them from the abdomen through a small incision, may worsen a woman’s prognosis if a cancer is morcellated unintentionally.

Using a national insurance database of 55 million women, Boston Medical Center (BMC) researchers looked at cases from 19,500 women who underwent laparoscopic hysterectomies or myomectomies, procedures which typically incorporate power morcellation, to determine how frequently women are diagnosed with cancer after undergoing a gynecologic surgery for a problem that is believed to be benign. The study revealed that 1 in 352 women had an unsuspected cancer at the time of gynecologic surgery for disease that was thought to be benign. The study is published online in advance of print in the journal Women’s Health Issues.

Our findings show that the risk for morcellating cancer is much higher than previously understood,” said Michael Paasche-Orlow, MD, MPH, general internal medicine physician at BMC and associate professor of medicine at Boston University School of Medicine (BUSM) who is the study’s senior author. “It makes sense to avoid morcellation for women with cancerous or pre-cancerous lesions. As it is difficult to ascertain in advance, safer alternatives are needed.”

The study also determined that more than half of the patients who were diagnosed with uterine cancer or endometrial hyperplasia, a pre-cancerous condition of the lining of the uterus, did not undergo endometrial testing prior to surgery. Thus, researchers suggest improving how physicians evaluate patients undergoing hysterectomies or myomectomies before they reach the operating room.

We are continually seeking opportunities to move gynecologic surgery forward,” said Rebecca Perkins, MD, a practicing gynecologist at BMC and associate professor of obstetrics and gynecology at BUSM who is the study’s lead author. “Because minimally invasive surgery has many advantages, future research should seek to improve techniques to create safer procedures for women.”

Perkins et al. Risk of Undetected Cancer at the Time of Laparoscopic Supracervical Hysterectomy and Laparoscopic Myomectomy: Implications for the Use of Power Morcellation. Women’s Health Issues. 2015; DOI: 10.1016/j.whi.2015.09.008 [pdf]

Gene therapy doubles survival in recurrent glioblastoma

An experimental gene therapy essentially doubled the overall survival of patients with recurrent glioblastoma compared to the current standard of care. Glioblastoma is an aggressive brain cancer that kills two-thirds of patients within five years. A patient’s outlook with recurrence of the disease is considered to be weeks or months.

CTRC medical oncologist Andrew J. Brenner, M.D., Ph.D., associate professor in medicine, neurology and neurosurgery at the UT Health Science Center School of Medicine, presented final results of a Phase 2 clinical research study that evaluated the gene therapy, called VB-111, in continuous and intermittent doses and in comparison to the treatment standard, the chemotherapy Avastin™. Patients receiving VB-111 survived 15 months on average, compared to 8 months on average for patients receiving Avastin alone. The CTRC and three other centers enrolled 62 patients with recurrent glioblastoma for the studies.

These are the patients with the most serious cases, whose glioblastoma has recurred after surgery and who, as a result, have a very short life expectancy,” Dr. Brenner said.

Dr. Brenner, principal investigator for the studies, presented the results this week at the European Cancer Congress meeting in Vienna, Austria. “In addition to the benefit in overall survival, VB-111 was safe and well-tolerated in the patients, and proved to be effective both as a single therapy for recurrent glioblastoma and in combination with Avastin,” he said.

VB-111 effectively starves the tumor by blocking its ability to grow new blood vessels, Dr. Brenner said. Tumors themselves begin the process by secreting a factor that activates the VB-111 drug. “This drug outsmarts the cancer,” Dr. Brenner said. 
“VB-111 is administered by intravenous infusion once every two months, which is convenient for patients and families,” he said. VB-111 has orphan drug status in the U.S. and Europe.

“The most frequent side effect in the study was fever, lasting one to two days following the infusion. This suggests an immune system response to the drug, which may play a role in its effectiveness,” Dr. Brenner said.

The improvement in overall survival is clinically significant. “These numbers compare favorably to any current benchmark in recurrent glioblastoma and may change the treatment paradigm for these patients,” Dr. Brenner said.

I am very proud of the work of Dr. Brenner and his team who are setting the stage for breakthrough advances in the treatment of brain cancer here at the CTRC,” said Ian Thompson Jr., M.D., CTRC director. “We are also especially thankful that Dr. Brenner is helping lead the large team of scientists and physicians who are developing next-generation cancer treatments at our cancer center.”

Phase 2 studies, conducted after first-in-human studies, add detail about the effectiveness and safety of experimental treatments for disease. VBL Therapeutics of Tel Aviv, Israel, maker of VB-111, recently launched a Phase 3 clinical research study of the drug to provide more detail.

The CTRC is currently the only site open for the Phase 3 trial, with the first patients enrolled here in San Antonio. Approximately 50 more sites in North America, Israel and Canada will be added in November 2015.

18th ECCO – 40th ESMO European Cancer Congress Vienna, Austria.

Genes of colon cancer recurrence differs among blacks, whites and Asians

The genetic makeup of colon cancer tumors and survival rates for patients with the disease differ by race, according to a study from researchers at the Mayo Clinic Cancer Center, published in the Journal of the National Cancer Institute.

These findings put the issue of race more prominently on the radar of investigators that cancer biology may contribute to race-based disparities,” says the study’s co-lead author, Harry Yoon, M.D., an oncologist at Mayo Clinic. “While it is too early to change the way we treat these patients, our results indicate that future studies are needed to examine potential biological drivers of these differences more closely.

According to the American Cancer Society, colon cancer is the third most common cancer in both men and women with more than 93,000 cases estimated to be diagnosed in 2015. Researchers have long known that blacks develop colon cancer at an earlier age and blacks with colon cancer are at higher risk of dying than whites. However, it has been difficult to identify why the differences in survival exist.

Researchers analyzed data from a large clinical trial of more than 3,000 patients with stage III colon cancer. The analysis revealed that tumors from whites, blacks, and Asians had different frequencies of mutations in two key cancer-related genes, BRAF and KRAS, which have been associated with worse outcomes. It also found that colon cancers were twice as likely to recur in black patients as in whites; however, the discrepancy was only evident in those under age 50.

Some of the potential reasons for this disparity include socio-economic factors, such as diagnosis at a later stage, decreased access to health care and suboptimal treatment.

The role of the biology of colon tumors according to race has not been examined as extensively,” says Dr. Yoon. “This biology can be reflected in the genetic makeup of tumors, as well as by whether and how quickly cancer returns after the patient has been treated.”

Dr. Yoon and his colleagues focused their efforts on finding out if colon cancers are genetically different based on race, as well as if race-based differences exist in recurrence rates. To do this, they examined data from a large clinical trial – Alliance N0147 – which included patients with stage III colon cancer from many centers in North America who all underwent surgery to remove their cancer and chemotherapy after surgery.

As part of the trial, the patients provided a self-description of their race as either white, Asian, or black or African-American. The researchers then evaluated the tumors from these participants to see if a mutation was present in the cancer-related genes BRAF and KRAS. They also noted if the cancer had returned after treatment.

Analysis of the data showed that tumors from whites, blacks and Asians were different in terms of the frequency of mutations in the BRAF and KRAS genes. Tumors from whites were twice as likely to have BRAF mutations; whereas, tumors from blacks had the highest frequency of KRAS mutations. Tumors from Asians were the most likely to have normal copies of both genes.

The analysis also indicated that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites. However, this discrepancy was only visible among young patients – those under age 50. Almost half of younger black patients experienced colon cancer recurrence within five years, compared to only 22 to 35 percent of whites or Asian patients of any age.

This difference could not be explained by the genetic mutations most frequently found in the tumors of the different races. The researchers adjusted for a number of other potential confounders, such as tumor grade, the degree of lymph node involvement, depth of tumor invasion, body mass index, location of the tumor within the colon, history of smoking, and anomalies in mismatch repair genes; however, none seemed to affect the outcome for young blacks.

Because all patients were treated and had their disease monitored in a clinical trial,” says Dr. Yoon, “suboptimal treatment, differences in cancer stage, or reduced access to care cannot adequately explain the disparity.”

“In addition to published data indicating that a limited number of genes are preferentially mutated in colon cancers from black versus white patients, our study revealed differences in the mutation frequencies of BRAF and KRAS oncogenes that provide prognostic information in colon cancer patients,” says Frank Sinicrope, M.D., an oncologist at Mayo Clinic and co-lead author. “Our data provide further evidence that colon cancers from blacks are intrinsically different and are associated with more aggressive clinical behavior in young black patients.

​Yoon et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015; 107 (10): djv186 doi:10.1093/jnci/djv186 [Abstract]

Young survivors of skin cancer at risk of developing other cancers

Risk decreased significantly with increasing age, but it remains higher compared with individuals who have never had non-melanoma skin cancer (NMSC).

NMSC is considered the most common type of skin cancer, relatively easy to treat if detected early, and rarely spreading to other organs. “Our study shows that NMSC susceptibility is an important indicator of susceptibility to malignant tumors and that the risk is especially high among people who develop NMSC at a young age,” said Professor Sinclair, Professor of Medicine at the University of Melbourne and Director of Dermatology at Epworth HealthCare.

The researchers collected hospital admission and death data from the All England Record-linked Hospital between 1999 and 2011, and constructed two cohorts: a cohort of 502,490 people with a history of NMSC, and a cohort of 8,787,513 people who served as controls. The risk for developing any cancer subsequent to NMSC decreases significantly with increasing age: 23 times higher risk for those under 25 years of age; 3.52 for those 25-44 years of age; 1.74 for those 45- 59 years of age; and 1.32 for those older than 60 years. Results are published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

They followed up the participants for five to six years, 67,148 from the NMSC cohort and 863,441 from the control cohort subsequently developed cancers.

They found that for those who had NMSC, the relative risk for developing cancers of the bladder, brain, breast, colon, liver, lung, pancreas, prostate, and stomach remained consistently elevated for the entire period of the study, and the risk for cancers of the brain, colon, and prostate increased with time.

The researchers also found that those who had NMSC under 25 years of age were 53 times more likely to get bone cancer, 26 times more likely to get blood cancers, 20 times more likely to get brain cancer, and 14 times more likely to get any cancer excluding those of the skin.

The risk increases for a large group of seemingly unrelated cancers; however, the greatest risk relates to other cancers induced by sunlight, such as melanoma.”

Early detection of cancers through screening of asymptomatic people works best when screening can be targeted at those at greatest risk. Our study identifies people diagnosed with NMSC at a young age as being at increased risk for cancer and, therefore, as a group who could benefit from screening for internal malignancy,” Professor Sinclair said.

Ong et al., (2014). Subsequent primary malignancies in patients with nonmelanoma skin cancer in England: A national record-linkage study. Cancer Epidemiol. Biomarkers Prev., 23: 490-498 [Abstract]

Four cups of coffee a day may keep prostate cancer away

Bioactive compounds in coffee may have anti-inflammatory and antioxidant effects

Coffee consumption is associated with a lower risk of prostate cancer recurrence and progression, according to a new study by Fred Hutchinson Cancer Research Center scientists that is online ahead of print in Cancer Causes & Control.

Corresponding author Janet L. Stanford, Ph.D., co-director of the Program in Prostate Cancer Research in the Fred Hutch Public Health Sciences Division, conducted the study to determine whether the bioactive compounds in coffee and tea may prevent prostate cancer recurrence and delay progression of the disease.

Stanford and colleagues found that men who drank four or more cups of coffee per day experienced a 59 percent reduced risk of prostate cancer recurrence and/or progression as compared to those who drank only one or fewer cups per week.

They did not, however, find an association between coffee drinking and reduced mortality from prostate cancer, although the study included too few men who died of prostate cancer to address that issue separately.

First study to assess the link between tea and prostate cancer outcomes

Regarding tea consumption, the researchers did not find an associated reduction of prostate cancer recurrence and/or progression. The study also did not draw any conclusions regarding the impact of tea drinking on prostate-specific death.

“To our knowledge, our study is the first to investigate the potential association between tea consumption and prostate cancer outcomes,” the authors wrote. “It is important to note, however, that few patients in our cohort were regular tea drinkers and the highest category of tea consumption was one or more cups per day. The association should be investigated in future studies that have access to larger populations with higher levels of tea consumption.”

The population-based study involved 1,001 prostate cancer survivors, aged 35-74 years old at the time of diagnosis between 2002-2005, who were residents of King County, Wash. Participants answered questions regarding their diet and beverage consumption two years prior to prostate cancer diagnosis using a validated food frequency questionnaire, and were interviewed about demographic and lifestyle information, family history of cancer, medication use and prostate cancer screening history.

The researchers followed up with patients more than five years after diagnosis to ascertain whether the prostate cancer had recurred and/or progressed. Those who were still living, willing to be contacted and had been diagnosed with non-metastatic cancer were included in the follow-up effort.

Of the original 1,001 patients in the cohort, 630 answered questions regarding coffee intake, fit the follow-up criteria and were included in the final analysis. Of those, 61 percent of the men consumed at least one cup of coffee per day and 12 percent consumed the highest amount: four or more cups per day.

The study also evaluated daily coffee consumption in relation to prostate cancer-specific death in 894 patients using data from the initial food frequency questionnaire. After the median follow-up period of eight-and-a-half years, 125 of the men had died, including 38 specifically from prostate cancer. Daily coffee consumption was not associated with prostate cancer-specific mortality or other-cause mortality, but with few deaths these analyses were limited.

“Our study differs from previous ones because we used a composite definition of prostate cancer recurrence/progression,” said first author Milan Geybels, a doctoral student at Maastricht University in the Netherlands who was a graduate student in Stanford’s Prostate Studies group at Fred Hutch when the study was conducted. “We used detailed information on follow-up prostate-specific antigen levels, use of secondary treatment for prostate cancer and data from scans and biopsies to assess occurrence of metastases and cause-specific mortality during follow up. Using these detailed data, we could determine whether a patient had evidence of prostate cancer recurrence or progression.”

The results are consistent with findings from Harvard’s Health Professionals Follow-up Study, which found that men who drank six or more cups of coffee per day had a 60 percent decreased risk of metastatic/lethal prostate cancer as compared to coffee abstainers.

Phytochemicals in coffee have anti-inflammatory and antioxidant effects

Further research is required to understand the mechanisms underlying the results of the study, but biological activities associated with consumption of phytochemical compounds found in coffee include anti-inflammatory and antioxidant effects and modulation of glucose metabolism. These naturally occurring compounds include:

  • Caffeine, which has properties that inhibit cell growth and encourage apoptosis, or programmed cell death. Previous studies have found that caffeine consumption may reduce the risk of several cancer types, including basal-cell carcinoma, glioma (a cancer of the brain and central nervous system) and ovarian cancer.
  • Diterpenes cafestol and kahweol, which may inhibit cancer growth.
  • Chlorogenic acid, which, along with caffeic acid, can inhibit DNA methylation, a biochemical process involved in the development and progression of many cancer types.

Additional studies needed to confirm whether coffee can prevent cancer recurrence

The researchers emphasize that coffee or specific coffee components cannot be recommended for secondary prevention of prostate cancer before the preventive effect has been demonstrated in a randomized clinical trial. Further, there’s ongoing debate about which components in coffee are anti-carcinogenic, and additional large, prospective studies are needed to confirm whether coffee intake is beneficial for secondary prevention.

Coffee drinking may even be problematic for some men, Geybels said.

“Although coffee is a commonly consumed beverage, we have to point out that increasing one’s coffee intake may be harmful for some men. For instance, men with hypertension may be vulnerable to the adverse effects of caffeine in coffee. Or, specific components in coffee may raise serum cholesterol levels, posing a possible threat to coronary health. Patients who have questions or concerns about their coffee intake should discuss them with their general practitioner,” he said.

The investigators also noted limits to their study, which included a lack of data on how coffee consumption might have changed following diagnosis, whether the coffee that participants consumed was caffeinated or decaffeinated, and how the coffee was prepared (espresso, boiled or filtered), a factor that may affect the bioactive properties of the brew.

Geybels et al., (2013). Coffee and tea consumption in relation to prostate cancer prognosis. Cancer Causes & Control, EPub Ahead of Print [Abstract]

Soy protein supplementation does not reduce risk of prostate cancer recurrence

Among men who had undergone radical prostatectomy, daily consumption of a beverage powder supplement containing soy protein isolate for 2 years did not reduce or delay development of biochemical recurrence of prostate cancer compared to men who received placebo, according to a study in the July 10 issue of JAMA.

“Prostate cancer is the most frequently diagnosed malignancy and the second most frequent cause of male cancer death in the United States and other Western countries but is far less frequent in Asian countries. Prostate cancer risk has been inversely associated with intake of soy and soy foods in observational studies, which may explain this geographic variation because soy consumption is low in the United States and high in Asian countries,” according to background information in the article.

“Although it has been repeatedly proposed that soy may prevent prostate cancer development, this hypothesis has not been tested in randomized studies with cancer as the end point. A substantive fraction (48 percent – 55 percent) of men diagnosed as having prostate cancer use dietary supplements including soy products, although the exact proportion is not known. However, no evidence exists that soy supplementation has any prostate cancer-related benefits for these men. Soy contains several constituents, including isoflavones, which possess anticancer activities in laboratory studies.”

Maarten C. Bosland, D.V.Sc., Ph.D., of the University of Illinois at Chicago, and colleagues examined whether daily consumption of a soy protein-based supplement would reduce the rate of recurrence or delayed recurrence of prostate cancer in men at high risk of recurrence after radical prostatectomy. The randomized trial was conducted from July 1997 to May 2010 at 7 U.S. centers and included 177 men. Supplement intervention was started within 4 months after surgery and continued daily for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or as placebo, calcium caseinate (n=90).

The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3 percent of participants developed biochemical recurrence (defined as development of a PSA level of ≥0.07 ng/mL) within 2 years of entering the trial. Twenty two (27.2 percent) of the participants in the intervention group developed confirmed biochemical recurrence, whereas 23 (29.5 percent) of the participants receiving placebo developed recurrence. “Among participants who developed recurrence, the median [midpoint] time to recurrence was somewhat shorter in the intervention group (31.5 weeks) than in the placebo group (44 weeks), but this difference was not statistically significant,” the authors write.

Adherence was greater than 90 percent. There were no differences in adverse events between the 2 groups.

“The findings of this study provide another example that associations in observational epidemiologic studies between purported preventive agents and clinical outcomes need confirmation in randomized clinical trials. Not only were these findings at variance with the epidemiologic evidence on soy consumption and prostate cancer risk, they were also not consistent with results from experiments with animal models of prostate carcinogenesis, which also suggest reduced risk,” the researchers write.

“One possible explanation for these discrepant results is that in both epidemiologic studies and animal experiments, soy exposure typically occurred for most or all of the life span of the study participants or animals; there are no reports of such studies in which soy exposure started later in life. Thus, it is conceivable that soy is protective against prostate cancer when consumption begins early in life but not later or when prostate cancer is already present. If this is the case, chemoprevention of prostate cancer with soy is unlikely to be effective if started later in life, given the high prevalence of undetected prostate cancer in middle-aged men.”

Bosland et al., (2013). Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy. JAMA310:170-178 [Abstract]