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Friday, September 22, 2017

Scientists from the cluster of excellence BIOSS Centre for Biological Signalling Studies at the University of Freiburg and the Freiburg University Medical Center have shown that inhibiting the epigenetic regulator KDM4 might offer a potential novel treatment option for breast cancer patients.

They used a newly established cell model that enables scientists to isolate cancer stem cells directly from patient tumor. Using this special culture system, they were able to test potential new cancer drugs. One of these, a novel inhibitor of the epigenetic regulator KDM4, co-developed in the lab of Professor Roland Schüle, PhD, showed promising results (Can Res 2017; doi:10.1158/0008-5472.CAN-17-1754).

Although the prognosis for breast cancer has been steadily improving in the last decades, patients with triple receptor-negative breast cancer form a subgroup who receive a considerably worse prognosis in most cases. Roughly 15 percent of all breast cancer patients have triple receptor-negative breast cancer, which lacks markers for a targeted therapy. In the last few years, a bulk of data pointing to a small population of cells in tumors that maintain tumor growth, are particularly resistant to chemotherapy, are responsible for relapses, and develop metastases. These cells, named cancer stem-like cells, share many characteristics with the body's normal stem cells. Due to their cancer-driving behavior, researchers have been focusing more and more on targeting these cells. However, there are currently only a few models available to study the biology of cancer stem cells.

Scientists from the University of Freiburg's new Center for Translational Cell Research have developed a model that allows scientists to isolate cancer stem cells from tumors obtained from breast cancer patients, thereby making biochemical and molecular analysis much more feasible. Jochen Maurer, PhD, and his research group were able to cultivate several cancer stem cell lines from triple receptor-negative breast cancer that are excellent representations of the original tumors they isolated from the patients.

In collaboration with Schüle and his team at the Center of Clinical Research of the Freiburg University Medical Center, the scientists were able to test several epigenetic inhibitors that had been newly developed by Schüle and his team on the cancer stem cell model. Epigenetics relates to the regulation of genes without involving changes in the DNA sequence and is regarded as one of the most important issues of the 21st century. It is believed that epigenetics play a huge role in the development and progression of cancer.

Schüle and his team have already conducted well-known studies on the epigenetic regulator LSD1. Now, they have discovered that an inhibitor of the epigenetic regulator KDM4 shows great promise in modulating breast cancer stem cell pathology. They were able to block proliferation of several cancer stem cell lines. In addition, the KDM4 inhibitor induces a change of the molecular make-up of the cancer stem cells and drives them out of stemness. Finally, they were also able to reduce tumor growth in their first in vivo xenograft analysis.​

Wednesday, September 20, 2017

By Catlin Nalley

Given BRCA mutations are linked to a higher lifetime risk of ovarian and breast cancers, many women with these gene mutations often consider preventive measures, including mastectomy or removal of the ovaries and fallopian tubes.

New research, however, suggests that for women with BRCA mutations who have already had ovarian cancer, the benefits of risk-reducing mastectomies may not outweigh the costs.

Researchers from the Duke Cancer Institute found that for many women in this patient population, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective (Ann Surg Oncol 2017; doi:10.1245/s10434-017-5995-z).

This study was prompted, in part, by the recent changes in NCCN guidelines that recommended that women with ovarian cancer undergo BRCA mutation testing, regardless of family history, noted senior author Rachel Greenup, MD, MPH, Assistant Professor of Surgery at Duke. With this shift in guidelines, more women will learn of their BRCA-mutation and increased risk of breast cancer following ovarian cancer diagnosis.

"Risk-reducing mastectomy is costly and can require many months of follow-up and recovery," Charlotte Gamble, MD, the study's lead author and a resident physician at Duke University School of Medicine said, in a statement. "Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer."

Study Methodology, Results

Researchers constructed a statistical model comparing risk-reducing mastectomy to surveillance that included mammogram and MRI, according to Greenup.

"The model incorporated factors like age at ovarian cancer diagnosis, time to risk-reducing mastectomy, BRCA mutation status, survival rates, and treatment costs," she explained. "Risk-reducing mastectomy was compared to breast cancer screening every 6 months from 1-15 years after ovarian cancer diagnosis."

Data were also separated into four categories based on the age at time of the initial ovarian cancer diagnosis: younger than 40, 40-50, 50-60, and 60-70.

The incremental cost-effectiveness ration, a cost-effectiveness measure, was also considered by study authors. "Health care interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature," according to researchers. This threshold was utilized in the study.

The benefits of risk-reducing mastectomy compared to screening alone depended on the age of the patient at the time of their ovarian cancer diagnosis and time to mastectomy, according to investigators.

"[We] found that, within the first 4 years after ovarian cancer diagnosis, prophylactic mastectomy was associated with a negligible gain in months of survival," reported Greenup. "It was, therefore, not found to be cost-effective among women of any age with BRCA 1 and 2 gene mutations."

For women diagnosed at age 60 or older, the gain in survival months was also negligible and procedure would not be cost-effective, regardless of time since ovarian cancer diagnosis.

Among women ages 40-50 with BRCA 1 and 2 mutations, the procedure was associated with a survival benefit of 2-5 months compared to screening, Greenup told Oncology Times. "This was found to be cost-effective when performed at least 5 years after an ovarian cancer diagnosis," she explained.

One limitation of the study, noted Greenup, is the model's dependency on previously published incidence rates and costs, which may not entirely reflect current numbers.

 Practice Implications

This study offers guidance to women and physicians who are debating the benefits and timing of prophylactic mastectomy following ovarian cancer treatment.

"Our study provides clarity on how a woman's age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure," Gamble said. "Within the first 5 years, nobody benefitted from risk-reducing mastectomy and, after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients."

"There is no right or wrong answer on how to manage breast cancer risk in this unique population," added Greenup. "However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.

"Certainly, this unique subset of women can focus on the treatment of their ovarian cancer and be reassured that prophylactic mastectomy provides minimal benefit in the immediate period after ovarian cancer diagnosis," she concluded.

Catlin Nalley is associate editor.




Wednesday, September 20, 2017

Rucaparib maintenance therapy increases progression-free survival in BRCA mutant recurrent ovarian cancer by 77 percent, according to late-breaking results from the ARIEL3 trial reported at the ESMO 2017 Congress in Madrid (Abstract LBA40_PR).

Most ovarian cancer presents as advanced disease and 80 percent of those patients will recur after first-line treatment. Patients often respond again to chemotherapy, particularly platinum-based, but they almost inevitably relapse again and eventually die of their disease. Maintenance treatments are needed to reduce recurrence in patients who have already relapsed.

The PARP enzyme helps to initiate the repair of DNA damage so that cells can continue to divide. DNA repair processes are inherently impaired in tumor cells with BRCA mutations. PARP inhibitors, such as rucaparib, block DNA repair and cells when BRCA mutations die.

Just over 20 percent of patients with ovarian cancer have BRCA mutations and are susceptible to PARP inhibitors. Some others with the disease are also susceptible, such as patients who respond to platinum-based chemotherapy and those with a high degree of genomic loss of heterozygosity (LOH)— meaning the tumor DNA is scarred and DNA repair mechanisms are faulty.

ARIEL3 included 564 patients with high-grade ovarian cancer who had responded to platinum-based chemotherapy in the second or third line of treatment. Patients were randomized 2:1 to rucaparib maintenance therapy or placebo. The primary endpoint was progression-free survival, which was measured sequentially in three groups if benefit was found in the previous group:

  1. BRCA mutant;
  2. BRCA mutant or BRCA wild type with high LOH (together called homologous recombination deficient or HRD); and
  3. Intention to treat (entire study population).

Rucaparib led to a statistically significant improvement in progression-free survival in all three groups. Progression-free survival increased from 5.4 months to 16.6 months, 13.6 months, and 10.8 months in groups 1, 2, and 3, respectively, with hazard ratios of 0.23, 0.32, and 0.36, respectively.

"The improvement in progression-free survival was greatest in the BRCA mutated group, who had a 77 percent increase, but it was seen across three subgroups that were evaluated," said first author Jonathan Ledermann, MD, FRCP, BSc, Professor of Medical Oncology, UCL Cancer Institute, London.

In exploratory analyses, patients without BRCA mutations (wild type) were divided into those with high and low LOH. As expected, patients with high LOH had more improvement in progression-free survival than those with low LOH. But in both high and low LOH subgroups, rucaparib was statistically significantly better than placebo.

"We had hoped that the LOH test would distinguish responders from non-responders but both high and low LOH groups benefitted," Ledermann said. "However, the magnitude of progression-free survival benefit was greater in the BRCA wild type/LOH high patients."

Rucaparib was well-tolerated and just 13 percent of patients had to discontinue the medication due to side effects. The safety profile of rucaparib in ARIEL3 was consistent with previous phase II studies.

"PARP inhibitors are the biggest development in ovarian cancer therapy since the introduction of platinum drugs in the late 1970s and early 1980s," Ledermann concluded. "Rucaparib is clearly an exemplary member of this exciting class of drugs that can be used to treat women with recurrent ovarian cancer in the maintenance setting."

Commenting on the results, Andrés Poveda, MD, Head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, Chair of the Gynaecologic Cancer Intergroup, Member of the ESMO Faculty on Gynecological Cancer, said: "ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefitted, especially those with BRCA mutations but also homologous recombination deficient (HRD) patients."

"In Europe, the PARP inhibitor olaparib is licensed as maintenance therapy but only for patients with germline BRCA mutations," he added. "We are awaiting a decision on niraparib, another PARP inhibitor. The addition of rucaparib would expand the population of patients receiving benefit from this type of drugs.

"Personalized medicine has arrived in high-grade serious ovarian cancer. Further studies are needed to identify predictive biomarkers of response to PARP inhibitors," Poveda emphasized. "Specifically, we need to know whether there are non-HRD factors that predict response."


Wednesday, September 20, 2017

Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little easier for physicians taking care of people with BRCA1/2 mutations.

Researchers in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, found a relationship between the genetics of tumors with germline BRCA1/2 mutations and whether the tumor retains the normal copy of the BRCA1/2 gene, and risk for primary resistance to a common chemotherapy that works by destroying cancer cells' DNA (Nat Comm 2017; doi:10.1038/s41467-017-00388-9).

Researchers estimate that 20 percent of ovarian cancers and 5 percent of breast cancers are attributable to germline mutations in BRCA1 and BRCA2, the focus of the current study.

There are many reasons patients may be resistant to treatment—the immune system, the complex landscape of a tumor, or a patient's own genes can all play a role. Without explicitly looking for it, the Penn team found another mechanism of resistance to a standard treatment for patients with BRCA-associated cancers. "Our primary question was not aimed at evaluating resistance to therapy, but we did end up there," said senior author Katherine Nathanson, MD, Deputy Director of the Abramson Cancer Center, and Director of Genetics at the Basser Center for BRCA.

Her group evaluated the genetic profiles of 160 ovarian and breast cancers associated with germline mutations in BRCA1 and BRCA2, in the largest study of these tumors to date. They were interested in determining what types of secondary, additional changes occur in primary BRCA1/2 germline mutation-associated cancers that might act in concert with mutant BRCA1 and BRCA2 to drive the cancers.

The team evaluated how frequently the non-mutated version of the gene lost its function in concert with the original BRCA1/2 germline mutation-associated cancers. Historically, it had been thought that all tumors associated with germline BRCA1/2 mutations lose the second version of the gene, or loss of heterozygosity (LOH). The investigators were surprised to find that was not the case in a surprisingly large percentage of patients. In addition, they found that other genetic and clinical features of patients whose tumors did not undergo LOH (LOH-negative) were significantly different from those that did undergo LOH (LOH-positive).

Notably, they evaluated the overall survival of patients with ovarian tumors with and without loss of heterozygosity. LOH-negative status was associated with worse overall survival in ovarian cancer patients treated with platinum chemotherapy, with a median of 39 months, compared to 71 months in the LOH-positive group who received the same treatment.

The researchers believe the patients with LOH-negative tumors (those with one working copy of BRCA1 or BRCA2 and the other copy carrying the germline mutation) had tumor cells that could still repair the chemotherapy-induced DNA damage in order to survive. In contrast, the investigators surmise that the LOH-positive group (with both gene copies disabled) responded better to the same therapy because their tumor cells died more readily.

"Identifying the LOH status of BRCA1/2 carriers may be useful to predict who might be at risk for primary resistance to DNA-damaging agents such as platinum, which has important implications for treatment of patients with these mutations," said the study's first author Kara N. Maxwell, MD, PhD, an instructor of Hematology/Oncology. "We only need to determine the LOH at a specific gene's location, which is more cost effective than sequencing a patient's whole genome, for example, and compatible with standard testing."

By looking at a person's individual genetics and type of cancer, the Penn team hopes to be able to better tailor care soon after an initial diagnosis to improve survival. Nathanson surmises that knowing a person's LOH status could guide treatment decisions. She suggests that certain drugs already in today's cancer treatment arsenal will likely work for patients who are at risk for resistance due to their LOH genetics; however, it's a matter of choosing the right one.

Monday, September 11, 2017

The preliminary results of a study presented at the ESMO 2017 Congress in Madrid show that socio-psychological factors have become more significant for patients today than physical side effects such as nausea and vomiting, which were among the top concerns in similar studies carried out previously. The side effects of chemotherapy seriously impact cancer patients' daily lives, and managing them is a longtime concern for doctors (Abstract 1472P_PR).

The side effects of chemotherapy seriously impact cancer patients' daily lives, and managing them is a longtime concern for doctors. Patient assessments on the subject have been carried out regularly since 1983. The new study showed that perceptions of chemotherapy side effects change not only over time, but also throughout the course of treatment.

"With the most recent analysis dating back to 2002, we felt it was time to collect new data and update the interview format," said study author Beyhan Ataseven, MD, from Kliniken Essen Mitte Evang, Huyssens-Stiftung in Essen, Germany. "Living conditions have changed, and so have the accompanying therapies linked to chemotherapy. As doctors, we want to know what our patients care about."

Contrary to previous studies, the team led by Ataseven focused exclusively on breast and ovarian cancer patients and added a longitudinal analysis by carrying out three separate interviews before, during and at the end of their chemotherapy.

At each interview, 141 patients scheduled for or undergoing chemotherapy were presented with two groups of cards respectively featuring physical and non-physical side effects. The patients selected their five most burdensome symptoms in each group and ranked them by importance. Out of these 10 main side effects, they were then asked to select the five most significant ones from both groups and to rank these as well.

"What we found is that, on the one hand, side effects like nausea and vomiting are no longer a major problem for patients—this can be explained by the fact that modern medication against these symptoms is very effective. On the other hand, hair loss is still a persistent, unsolved issue that particularly affects patients at the start of their treatment," said Ataseven. "As time passes and patients get used to this, however, their concerns evolve and other side effects become more significant.

"Looking at patients' perceptions over the entire course of their chemotherapy, the most difficult side effects they deal with are sleep disorders—which become increasingly important over time—and anxiety about the effects of their illness on their partner or family, which remains a top issue throughout," Ataseven explained.

"As doctors, these findings might lead us to consider possible improvements to the accompanying therapies we offer our patients. For instance, sleeping tablets were not until now a part of the routine regimen. There is also a clear case for providing stronger psychological support to address patients' social anxieties and family-related concerns," she said.

ESMO will soon publish a position paper on the need to integrate supportive and palliative care for patients, from diagnosis and throughout the course of the disease. Karin Jordan, MD, PhD, Chair of the ESMO Faculty Group on Palliative and Supportive Care and senior leading physician at the University of Heidelberg's Department of Medicine, commented on the study: "The results show that there might be a gap between what doctors think is important or disturbing for patients, and what patients really think. Physical, psychological, social, and spiritual support is needed at every stage of the disease," she said. "Going forward, similar studies also need to be done for other types of cancer—including analyses of how an optimal management of side effects influences the disease trajectory."