A cancer diagnosis makes diabetes patients less adherent to their prescribed diabetes drugs

Diabetes patients become less adherent to their diabetes medications following a diagnosis of cancer, concludes a new study published in Diabetologia (the journal of the European Association for the Study of Diabetes). The research is led by Marjolein Zanders, Netherlands Comprehensive Cancer Organisation, Eindhoven, the Netherlands, Jeffrey Johnson, School of Public Health, University of Alberta, Edmonton, Canada and colleagues.

Cancer patients with diabetes have a significantly higher overall mortality risk compared with patients without diabetes. Most research on diabetes and cancer has focussed on the influence of diabetes and glucose lowering drugs (GLDs) on outcomes after cancer diagnosis; yet cancer itself might affect outcomes associated with diabetes, in part by affecting adherence to their prescribed GLDs. Although one previous study has found that breast cancer patients were less likely to take their diabetes drugs as directed after being diagnosed with cancer, this study lacked a control group without cancer. In this new study, the authors aimed to evaluate changes in adherence to GLDs following a cancer diagnosis, taking into account changes in adherence to GLDs among similar diabetic patients without cancer.

All new users of GLDs (1998-2011) who lived in the Eindhoven Cancer Registry-PHARMO Database Network (which includes out-patient pharmacy data) catchment area were selected. From the 52,228 GLDs users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study, with a mean age of 68 years in each group. The Medication Possession Ratio (MPR) was used as an indicator for medication adherence. The MPR represents the amount of medication patients had in possession over a certain time period. Thus, a 10% decline in MPR translates to a difference of 3 days in a 30-day month that are not covered by the use of GLDs (that is, 3 days in that month where the patients did not take their diabetes medications). For every month the MPR for cases was compared with the MPR for matched controls, which represented the overall trend among individuals with diabetes but without cancer.

The data showed that before cancer diagnosis the MPR increased by 0.10% per month. Besides a significant drop in MPR at the time of cancer diagnosis of -6.3%, there was an ongoing, yet lower, monthly decline in MPR (-0.20%) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11-15%, were seen among patients with stage IV cancer disease and gastrointestinal or pulmonary cancers.

Different effects were seen for the various tumour types studied: while no important decline in MPR was seen at the time of diagnosis for prostate (+2.1%) and breast cancer (-0.5%), large drops were seen among patients with oesophageal, stomach, pancreas or liver cancer (-12.5%;) and pulmonary cancers (-15.2%). Among those patients with large adherence drops, the MPR after cancer diagnosis decreased approximately 0.5% monthly, indicating ongoing declining medication adherence in such cases (oesophageal, stomach, pancreas or liver cancer -0.45%; pulmonary cancers -0.54%).

Within cancer subgroups, the largest declines in MPR at the time of cancer diagnosis were seen for liver and oesophageal cancer (-35% and -19% respectively), while for each extra month after cancer diagnosis, the largest decline in MPR of almost 1% each month was seen among patients with pancreatic cancer (-0.97%). Moreover, the higher (more serious) the stage of cancer, the greater the observed decline in medication adherence at cancer diagnosis. Among patients with stage IV cancer disease, the drop in MPR was -10.7%, while each extra month after cancer diagnosis the MPR declined an additional -0.64%.

This population-based study revealed that among new GLDs users, the diagnosis of cancer negatively influenced medication adherence, with a decrease in MPR of 6% at the time of cancer diagnosis. This translates to a difference of 2 days in a month that are not covered by the use of GLDs following a diagnosis of any cancer. Importantly, the influence of cancer on GLDs adherence seemed to be influenced by the type of cancer, with more pronounced effects among patients with oesophageal, stomach, pancreas or liver cancer and pulmonary cancers. Also, more advanced cancer stages at diagnosis resulted in substantially lower MPRs at the time of cancer diagnosis.

The authors suggest that the devastating effects of a serious cancer diagnosis could relegate the importance of taking medication for diabetes or other conditions. “Users of GLDs with more lethal cancers might prioritise the fight against cancer over the effort required to have a good metabolic control for their diabetes,” they explain. “The MPR might be a good indicator for medication adherence, although the physician could have advised the patient to stop the treatment with GLDs, which could not be investigated within the study. Reasons for stopping their treatment for diabetes are unknown – is it because of frequent hypoglycaemic events due to cancer or intolerable oral intake of drugs, for example among oesophageal or stomach cancer patients?

The authors conclude: “This study revealed that the medication adherence among users of GLDs was influenced by cancer diagnosis. Although the impact of cancer was more pronounced among cancers with a worse prognosis and among those with more advanced cancer stages, the difference in prognosis associated with these cancers seemed to only partly explain the impact of cancer on medication adherence. The decline in adherence seen among users of GLDs with cancer might negatively impact survival and (partly) explain the established association between diabetes, cancer and mortality. In future studies, the reason for the decline in MPR needs to be further elucidated among the different cancer types – is it the patient who prioritises the fight against cancer or the advice of the physician to stop the treatment?

Zanders et al. Impact of cancer adherence to glucose-lowering drug treatment in individuals with diabetes, Diabetologia. 2014; DOI 10.1007/s00125-015-3497-8 [Article Download]

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Key factor discovered in the formation of metastases in melanoma

Patients who visit the doctor because of malignant skin cancer often go too late – the aggressive cancer has already formed numerous metastases in their bodies.

This rapid, malignant metastatic formation of melanoma, was previously put down to the high mutation rate that is characteristic of melanoma, i.e. genetic changes that stimulate the growth of cancer cells. Various cancer drugs therefore target the signaling pathways activated in the process, some of which have recorded astonishingly positive results in the clinic and are able to prolong the lives of seriously sick patients.

Unfortunately, however, in most cases a kind of resistance develops: Eventually, the cancer cells no longer respond to the drug and the tumor spreads again. Evidently, the cancer cells have found new ways to grow. A team of researchers headed by Professor Lukas Sommer from the University of Zurich’s Institute of Anatomy has now found a possible explanation for this dynamic behavior in cancer cells: The scientists believe that, depending on the prevalent conditions, cancer cells are able to “read” different genes and use them to their own end.

A highly active epigenetic factor in cancer cells

The readability of genes is controlled by epigenetic factors, namely factors which do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. Consequently, the Zurich-based researchers studied whether epigenetic factors are especially active in melanoma cells – and stumbled across EZH2, an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells.

Joining forces with dermatologists and oncologists from the University Hospital in Zurich and backed by the University Research Priority Program “Translational Cancer Research”, Sommer’s team was able to demonstrate that, in melanoma cells, the epigenetic factor EZH2 controls genes that govern tumor growth as well as genes that are important for the formation of metastases. In their study, the researcher exploited this central position of EZH2 to combat the cancer: They used a pharmacological inhibitor to suppress the activity of EZH2. As a result, the researchers were able to prevent the growth and malignant spread of the cancer in the animal model and human melanoma cells.

To our astonishment, we were able to use the approach to influence the progression of the disease, even if tumors had already developed,” explains Sommer. Epigenetic factors like EZH2 therefore appear to be highly promising targets for future cancer treatments, especially combined with other drugs that are already available.

Zingg et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nature Communications, 2015. Doi: 10.1038/ncomms7051 [Abstract]

World’s first-in-human clinical trial of a novel vaccine targeting top cancers

First-in-human clinical trial using adenovirus to receive endorsement from both US Food and Drug Administration and Health Sciences Authority

The National Cancer Centre Singapore (NCCS) has launched a clinical trial of a new cancer vaccine administered to human patients for the first time in the world. Cancer immunotherapy (the harnessing of the body’s defence system to fight the patient’s cancer, has emerged as one of the most exciting medical breakthroughs in the past two years.

In fact, the prestigious Science journal voted Cancer Immunotherapy the Breakthrough of the Year for 2013. Cancer Immunotherapy includes cancer vaccines, a form of treatment aimed at stimulating the body’s immune cells to attack a target protein on cancer cells. This particular cancer vaccine encodes one of the most common proteins, MUC-1 that is expressed on many cancers, including ovarian, breast, prostate, colon, pancreas and lung cancer, but not expressed on normal cells.

The Singapore Clinical Research Institute (SCRI), a wholly-owned subsidiary of MOH Holdings, sponsored this clinical trial providing support that included project oversight, study drug importation, quality assurance and providing the medical expertise required in conducting a cancer trial.

Dr Toh Han Chong, NCCS Principal Investigator of the phase I clinical trial, who is also a Senior Consultant in the Division of Medical Oncology, said, “What makes this vaccine unique is that MUC-1 is attached to a protein that is intentionally designed to further enhance and boost the efficiency and power of the body’s immune system.” This protein is called CD40-ligand (CD40L), to form a construct called MUC-1+CD40L.

This construct fits into the backbone of a hardy virus called adenovirus, which further improves the body’s immune system specifically against MUC-1 expressed on the surface of the cancer, as demonstrated in convincingly superior animal study results. This vaccine has been developed by a United States biotech company, MicroVAX, and is injected under the patient’s skin. The Singapore Clinical Research Institute (SCRI) is the sponsor for this clinical study.

So far, four patients have been treated with this cancer vaccine, the first time ever that human patients have been given this novel treatment. Of the four patients, two are diagnosed breast cancer and the remaining two have ovarian cancer. All four patients have tolerated this vaccine well, with no significant side effects. One patient with advanced breast cancer with cancer spread to her skin developed a skin rash about 2 weeks after treatment which disappeared a few days later.

This skin rash may represent an immune reaction of the vaccine against her breast cancer cells which may be a good thing“, explained Dr Toh. CEO of MicroVAX, Mr Jake Frank commented on this first-in-human study, “MicroVAX wishes to express its gratitude to the patients and their families who are participating in the testing of its TAA/ecdCD40L cancer vaccine in the phase I clinical trial currently being carried out under the direction of Dr Toh and his world class team at the National Cancer Centre Singapore with the support of the Singapore Clinical Research Institute.

In preclinical studies, MicroVAX’s TAA/ecdCD40L vaccine was found to induce a potent immune response that surpassed that induced by other immunological strategies. The TAA/ecdCD40L is unique as it can target and destroy pre-existing cancerous tumours as well as prevent the development of cancer. In view of these unique features of the TAA/ecdCD40L vaccine platform, MicroVAX has been committed to bringing this vaccine technology to the clinic, and wishes to recognise the pivotal contributions of the SCRI and the NCCS in making this clinical trial possible.”

Dr Teoh Yee Leong, Chief Executive Officer, SCRI said, “This trial showcases the strong tripartite partnership between an Academic Research Organisation like SCRI with a biotech company like MicroVAX and a prestigious healthcare institution like NCCS in conducting clinical trials in Singapore. It is also the first time SCRI is sponsoring a clinical trial to support the clinical trial community in Singapore and importantly patients participating in these trials are the ones to most benefit.”

One of the cancer patients who received this cancer vaccine is 52-year-old Jane (her anglicised name) who lives in Helsinki, Finland. Jane has stage 4 ovarian cancer. Her husband had found this phase I clinical trial open for patient recruitment on the US National Institute of Health clinical trials website. Jane, who has been flying into Singapore every fortnightly since October last year, remains well and stable with no side effects from the vaccine whatsoever.

Another patient who participated in this trial is 60-year old Mrs Janet Quah who has stage 4 breast cancer. Both patients are happy to be interviewed for this media release.

Breast cancer diagnoses, survival varies by race, ethnicity

Among nearly 375,000 U.S. women diagnosed with invasive breast cancer, the likelihood of diagnosis at an early stage, and survival after stage I diagnosis, varied by race and ethnicity, with much of the difference accounted for by biological differences, according to a study in JAMA.

In the United States, incidence rates of breast cancer among women vary substantially by racial/ethnic group. Race/ethnicity and sociodemographic factors may influence a woman’s adherence to recommendations for clinical breast examination, breast self-examination, or screening mammogram and the likelihood of her seeking appropriate care in the event that a breast mass is noticed. A growing body of evidence suggests that biological factors may also be important in determining stage at diagnosis (i.e., the growth rate and metastatic potential of small-sized breast cancer tumors may vary between women due to inherent differences in grade and other or unknown pathological features), according to background information in the article.

Javaid Iqbal, M.D., of Women’s College Hospital, Toronto, and colleagues examined the proportion of breast cancers that were identified at an early stage (stage I) in different racial/ethnic groups in the United States and whether ethnic differences may be better explained by early detection or by intrinsic biological differences in tumor aggressiveness. The study included women diagnosed with invasive breast cancer from 2004 to 2011 who were identified in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database (n = 452,215). For each of 8 racial/ethnic groups, biological aggressiveness (triple-negative cancers [negative for estrogen receptor, progesterone receptor, and ERBB2 (formerly HER2 or HER2/neu)], lymph node metastases, and distant metastases) of small-sized tumors of 2.0 cm or less was estimated. In addition, the odds were determined for being diagnosed at stage I compared with a later stage, as was the risk of death from stage I breast cancer by racial/ethnic group.

Of 373,563 women with invasive breast cancer, 268 675 (71.9 percent) were non-Hispanic white; 34,928 (9.4 percent), Hispanic white; 38,751 (10.4 percent), black; 25,211(6.7 percent), Asian; and 5,998 (1.6 percent), other ethnicities. Average follow-up time was 40.6 months. The researchers found that Japanese women were significantly more likely to be diagnosed at stage I (56.1 percent) than non-Hispanic white women (50.8 percent), while black women were less likely to be diagnosed at stage I (37.0 percent), as were women of South Asian ethnicity (Asian Indian, Pakistani) (40.4 percent).

The 7-year actuarial risk for death from stage I breast cancer was highest for black women (6.2 percent) compared with white women (3.0 percent); it was 1.7 percent for South Asian women. The probability of a woman dying due to small-sized breast cancer tumors (2.0 cm or less) was significantly higher for black women (9.0 percent) compared with non-Hispanic white women (4.6 percent).

The authors write that much of the difference in diagnosis and survival could be statistically accounted for by intrinsic biological differences such as lymph node metastasis, distant metastasis, and triple-negative behavior of tumors.

Iqbal et al. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015;313(2):165-173. doi:10.1001/jama.2014.17322 [Article]

Many cancer survivors have unmet physical and mental needs related to their disease and its treatment

Even decades after being cured, many cancer survivors face physical and mental challenges resulting from their disease and its treatment. That’s the conclusion of a new study published early online in CANCER, a peer-reviewed journal of the American Cancer Society. The findings could help clinicians and other experts develop interventions that are tailored to the specific types of problems and concerns that cancer survivors may experience.

Increasingly, cancer patients are living many years after cancer treatment, with the number of US survivors expected to top 19 million by 2024. While many survivors do well after treatment, some experience continuing problems that can significantly impair their quality of life well beyond the magical 5-year survival milestone. These problems and challenges can vary by the type of cancer patients had and the treatments they received.

To assess the unmet needs of cancer survivors, Mary Ann Burg, PhD, LCSW, of the University of Central Florida in Orlando, and her colleagues looked at the responses from an American Cancer Society survey, wherein 1514 cancer survivors responded to the open-ended question, ‘Please tell us about any needs you have now as a cancer survivor that ARE NOT being met to your satisfaction.’ “This study was unique in that it gave a very large sample of cancer survivors a real voice to express their needs and concerns,” said Dr. Burg.

Survivors most frequently expressed physical problems, with 38 percent saying they were an issue. (Problems related to sexuality and incontinence among prostate cancer survivors were especially common.) Financial problems related to the costs of treatment also persisted long after treatment for 20 percent of respondents, with Black and Hispanic survivors being especially hard-hit. Anxiety about recurrence was a common theme expressed by survivors regardless of the type of cancer they had or how many years they had survived cancer. The number and type of unmet needs were not associated with time since cancer treatment.

Overall, we found that cancer survivors are often caught off guard by the lingering problems they experience after cancer treatment. In the wake of cancer, many survivors feel they have lost a sense of personal control, have reduced quality of life, and are frustrated that these problems are not sufficiently addressed within the medical care system,” said Dr. Burg. She noted that improvements are needed concerning public awareness of cancer survivors’ problems, honest professional communication about the side effects of cancer, and the coordination of medical care resources to help survivors and their families cope with their lingering challenges.

Burg et al. Current unmet needs of cancer survivors: Analysis of open-ended responses to the American Cancer Society Study of Cancer Survivors II. Cancer. 2015;EPub Ahead of Print [Abstract]