Social service barriers delay care among women with abnormal cancer screening

A recent study performed by researchers at Boston Medical Center (BMC), Boston University School of Medicine (BUSM), Boston University School of Public Health (BUSPH), and Tufts Medical Center found that women with multiple barriers to healthcare, especially those with social barriers such as problems with housing and income, experienced delays in cancer screening follow up compared to those with fewer barriers or no social barriers.

The study, which appears online in the Journal of General Internal Medicine, was led by Sarah Primeau, MSW, research assistant in the department of general internal medicine at BUSM.

Previous studies on healthcare barriers have shown that training individuals from the community, known as patient navigators, to provide emotional and logistical support to patients is an effective way to care for patients in a culturally sensitive way. However, these studies have not addressed whether patient navigators are also effective in addressing social service barriers such as financial problems, employment issues, health insurance, housing constraints and adult and child care.

“Social barriers are more complex than other obstacles to healthcare such as transportation or language and will likely require interventions that healthcare providers and patient navigators aren’t traditionally trained to provide,” said Primeau.

The study looked at 1,493 subjects enrolled in the Boston Patient Navigation Research Program (PNRP), a study performed at BMC from 2007-2010 that used patient navigators to help women with breast and cervical cancer screening abnormalities. The researchers used the data to separate the women into groups based on how many social barriers the navigator was able to identify. They then examined the data to see how long it took for each patient to reach a final diagnosis from the time of the initial abnormal screening test.

The researchers found that it took longer to achieve a final diagnosis in the patients with multiple barriers to healthcare, and that having one or more social barrier further increased the follow up time. The results of this study indicate that there is a continued need to better understand and overcome complex social obstacles to patient care.

“The findings suggest that not all women benefit equally from patient navigation and there is a need for more research into the innovation of cancer care delivery, and into a possible new model of patient navigation enhanced by legal advocacy,” said senior author, Tracy A. Battaglia, MD, director of the Women’s Health Unit at BMC and associate professor of medicine and epidemiology at BUSM.

Primeau et al., (2013). Social service barriers delay care among women with abnormal cancer screening. J. Gen. Intern. Med., EPub Ahead of Print, DOI: 10.1007/s11606-013-2615-x [Abstract]

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Ionizing radiation exposure promotes fusion oncogene formation

The accident at the Chernobyl nuclear power plant exposed hundreds of thousands of individuals to high levels of ionizing radiation. In the years immediately following the disaster, there was a sharp increase in the number of papillary thyroid cancers (PTC) in patients that were children at the time of the explosion.

In a recent issue of the Journal of Clinical Investigation, James Fagin and colleagues at Memorial Sloan-Kettering Cancer Institute, examined tissues from Ukrainian PTC patients that were children at the time of the Chernobly catastrophe and identified their cancer-driving mutations.

The authors found that the majority of patient tumors had chromosomal rearrangements that resulted in fusion oncogenes. Many of these fusion events promoted upregulation of MAPK signaling, which is a common cancer-associated pathway. In contrast, fusion oncogenes were less common in PCT tumors from patients from the same geographical region, but had not been exposed to radiation.

In the accompanying commentary, Massimo Santoro and Francesca Carlomagno of the University of Naples discuss how this study provides new insight into how ionizing radiation exposure promotes cancer development.

Ricarte-Filho et al., (2013). Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J. Clin. Invest., doi:10.1172/JCI69766 [Article]

Preclinical study finds drug helps against pancreatic cancer

An investigational drug that disrupts tumor blood vessels shows promise against a rare type of pancreatic cancer, scientists at Albert Einstein College of Medicine of Yeshiva University have found. Their results were presented October 20 during a poster session at an international cancer conference.

The drug Zybrestat selectively targets and collapses tumor blood vessels, depriving the tumor of oxygen and making its cells die. In experiments involving a mouse model of pancreatic neuroendocrine tumors, Einstein scientists found that infusing mice with Zybrestat three times per week for four weeks resulted in significant antitumor activity compared with control mice given a placebo.

The findings were presented in Boston at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics. Presenting for Einstein was ZiQiang Yuan, M.D., research assistant professor of surgery at Einstein. The senior author is Steven K. Libutti, M.D., professor of genetics at Einstein and professor and vice chair of surgery at Einstein and Montefiore Medical Center, the University Hospital and academic medical center for Einstein.

Pancreatic cancer is the fourth-leading cause of cancer death in the U.S. According to the National Cancer Institute, more than 45,000 Americans will be diagnosed with pancreatic cancer in 2013 and more than 38,000 will die of the disease. Exocrine pancreatic cancer, the more common and usually fatal type, begins in the ducts that carry pancreatic juices. The Einstein study involved endocrine pancreatic cancer—the much less common and more curable form of the disease that originates in pancreatic cells that make hormones (and that caused the death of Apple co-founder Steve Jobs).

All the mice in the study had insulinomas—endocrine tumors that form in pancreatic cells that make insulin, the hormone that controls glucose levels in the blood. This type of tumor can make the pancreas over-secrete insulin. The Einstein researchers found that treating the mice with Zybrestat caused a significant and sustained decrease in circulating insulin and also significantly reduced tumor size.

Zybrestat has been evaluated in clinical trials involving patients with anaplastic thyroid cancer, a highly aggressive cancer for which there are no approved treatments. The drug is made by OXiGENE, Inc., a biotech company based in San Francisco, CA.

Dr. Libutti is also director of the Montefiore Einstein Center for Cancer Care and associate director, clinical services at the Albert Einstein Cancer Center. This research was supported in part by OXiGENE, Inc. through a sponsored research agreement with Einstein. The authors report no conflicts of interest.

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Boston, MA, USA, October 19-23, 2013.

Study ties bone marrow transplant to negative sexual side effects

Radiation, graft-versus-host disease cited as particularly damaging

New research ties preparative procedures and complications associated with blood or bone marrow transplantation (stem cell transplantation, SCT) with diminished sexual health in both men and women who have undergone the lifesaving procedure. Study data, published online today in Blood, the Journal of the American Society of Hematology (ASH), confirm chronic graft-versus-host disease (GVHD), a serious complication that occurs when donor cells attack the recipient’s cells, as a potential source of sexual dysfunction and are the first to demonstrate an association between total body irradiation and sexual dysfunction in men. This study is one of the longest and is the most inclusive to date evaluating sexual well-being in SCT survivors using rigorous, well-validated sexual function assessment tools.

SCT is an increasingly effective form of treatment for patients with blood cancer such as leukemia, lymphoma, and myeloma. The procedure, which involves the transplantation of cells taken either from a patient’s own blood or bone marrow (autologous transplantation) or from a matched donor (allogeneic transplantation), effectively “replaces” damaged cells with healthy cells. While SCT was once associated with high mortality, survival rates have steadily increased, prompting research seeking to study and maximize survivors’ quality of life.

“Thanks to improved transplant survival rates, we have now been able to focus our efforts on examining how the procedure affects key aspects of recipients’ overall quality of life, including sexual health,” said lead study author F. Lennie Wong, PhD, of City of Hope in Duarte, California. “Previous findings point to the unfortunate fact that, while recipients may physically recover, their sexual health might not rebound as much or as quickly. Data have been limited to this point, prompting us to take a closer look at this issue in a larger, more diverse group of autologous and allogeneic transplant survivors over an extended period.”

To further investigate long-term effects of SCT on the sexual health of survivors, a team of researchers led by senior author Smita Bhatia, MD, MPH, surveyed 277 adult patients (152 men and 125 women; median age 48) who underwent SCT at City of Hope for blood cancer between February 2001 and January 2005 about their sexual activity. Participants completed two questionnaires that together evaluated specific areas of sexual function (sexual cognition/fantasy, sexual arousal, sexual behavior/experience, orgasm, and drive/relationship) as well as sexual satisfaction at a median time of 17 days pre-transplant and at six, 12, 24, and 36 months post-transplant. A third questionnaire assessed overall health-related quality of life.

Investigators’ analysis of questionnaire results (led by Dr. Wong) confirmed previous studies in demonstrating a definitive impact of SCT on survivors’ post-transplant sexual activity. During the three-year post-transplant analysis period, the percentage of men who self-reported being “sexually active” (defined as having sex with a partner at least once in the preceding month) declined 7 percentage points, with 61 percent of men reporting sexual activity pre-transplant and 54 percent reporting activity post-transplant. The opposite – a 15 percentage point increase in sexually active individuals – was observed in women, with 37 percent reporting sexual activity pre-transplant and 52 percent reporting activity post-transplant.

In addition to further crystallizing transplantation’s impact on survivors’ sexual health, study data specifically associated diminished sexual function and satisfaction with transplant-related total body radiation in men and chronic GVHD with diminished sexual function in men and both sexual function and satisfaction in women.

Investigators observed a nearly 18 percent decline in sexual function in men surveyed who had received total body radiation. The same group also reported an approximate 32 percent decrease in sexual satisfaction, a 26 percent decrease in sexual behavior/experience, a 26 percent decrease in quality of orgasm, and 17 percent decrease in sex drive/relationship since their transplant. Despite these effects in men, radiation had no such reported effect in women, an effect that investigators hypothesize may be explained by inherent physiologic differences in the pathogenesis of sexual dysfunction among men and women.

In addition to documenting concrete effects of radiation on sexual function and satisfaction, investigators also observed negative sexual effects among those surveyed who had experienced chronic GVHD. Men surveyed who had developed the dangerous post-transplant complication reported a 21 percent decrease in sexual cognition/fantasy and a 24 percent decrease in the quality of orgasm since their transplant. Similarly, investigators observed a 27 percent decline in post-transplant sexual satisfaction among women surveyed who had experienced chronic GVHD, with survey respondents also indicating a 27 percent decline in sexual arousal.

When compared to men, the women surveyed suffered significantly worse effects overall, despite the fact that their sexual activity increased over the three-year survey period. Investigators concluded that this increase in activity may be explained by a corresponding improvement in female psychological quality of life post transplant.

From this research, investigators conclude that nearly half of SCT survivors are sexually inactive at three years post transplant and suggest that patients may benefit from speaking with their doctors about sex.

“It is not often that the transplant team and patient will have a conversation about how this procedure could impact their sex life, even after recovery; however, we hope these findings will help encourage patients and their doctors to openly discuss concerns related to sexual dysfunction and address them with specialists who can help,” said Dr. Wong.

Wong et al., (2013). Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft vs. host disease and total body irradiation. Blood, EPub Ahead of Print [Abstract

Data reaffirms test’s ability to identify benign thyroid nodules

A Gene Expression Classifier test can drastically reduce the problem of unnecessary surgeries in thyroid nodule assessment

The latest study co-led by a CU School of Medicine researcher has confirmed that a Gene Expression Classifier (GEC) test can drastically reduce the problem of unnecessary surgeries in thyroid nodule assessment. These indeterminate nodules are being evaluated with a new molecular diagnostic test that measures the expression levels of 142 genes. This test is able to identify which initially indeterminate nodules are highly likely to be benign, and thus allows patients to avoid unnecessary diagnostic surgery.

This multi-site study co-led by Bryan R. Haugen, MD, professor of medicine and pathology at the University of Colorado School of Medicine provides the first long-term look at how these patients fared, and its findings reaffirm the performance of the Afirma Gene Expression Classifier (GEC). Haugen said “Each year, tens of thousands of patients with thyroid nodules have surgery to remove all or part of their thyroids. This is due to fine needle aspiration (FNA) cell test results that are indeterminate or inconclusive yet raise suspicions for thyroid cancer. Often times, most of these nodules prove to be benign. Our findings suggest that when the GEC identifies an otherwise indeterminate thyroid nodule as benign – which it does about 50% of the time – it is comparable in accuracy to a benign diagnosis by cytopathology, This fact and the degree to which physicians and patients in the study opted against surgery when the molecular test result was benign underscore the test’s potential to drastically reduce the problem of unnecessary surgeries in thyroid nodule assessment.”

Researchers analyzed all patients who had received Afirma GEC testing following indeterminate FNA biopsy results at five academic medical centers between 2010 and 2013. The GEC identified 174 of 339 (51%) indeterminate nodules as benign and, among these, 71 had documented clinical follow-up for an average of 9 months. Of these, only one nodule proved cancerous, demonstrating a very high negative predictive value (NPV) for the GEC. This finding is consistent with results from an earlier prospective, multicenter clinical study. Additionally, in the new study only 6% of patients with nodules identified as benign by the GEC test underwent surgery. This is a substantial reduction compared to traditional surgical rates for patients with cytologically indeterminate thyroid nodules.

Thyroid nodules are common, but only approximately 5-15% prove malignant. Most nodules are evaluated using FNA, with approximately 525,000 thyroid nodule FNAs performed in the U.S. in 2011 to rule out cancer. In most cases, the results are benign, yet in approximately 15-30% of cases the results are indeterminate – not clearly benign or malignant. Because of the risk of thyroid cancer, most of these patients have historically been recommended for surgery to remove all or part of the thyroid to obtain a final diagnosis. However, such indeterminate nodules prove ultimately benign in 70-80% of cases. For these patients, the surgery was not needed and they were unnecessarily exposed to the cost, risk and morbidity of this intervention. Additionally, most patients subsequently require lifelong thyroid hormone therapy.

The study is published online in the Journal of Clinical Endocrinology & Metabolism and its findings were presented recently at the 83rd Annual Meeting of the American Thyroid Association, held in Puerto Rico.

The long-term findings built on the previous study which demonstrates the Afirma Gene Expression Classifier’s accuracy was published in the New England Journal of Medicine.

Alexander et al., (2013). Multicenter Clinical Experience with the Afirma Gene Expression Classifier. JCEM, EPub Ahead of Print, doi:10.1210/jc.2013-2482 [Abstract]

Overuse of radiation therapy when urologists profit from self-referral

IMRT use is 2.5 times greater when self-referral’s financial incentives are involved

A comprehensive review of Medicare claims for more than 45,000 patients from 2005 through 2010 found that nearly all of the 146 percent increase in intensity-modulated radiation therapy (IMRT) for prostate cancer among urologists with an ownership interest in the treatment was due to self-referral, according to new research, “Urologists’ Use of Intensity-Modulated Radiation Therapy for Prostate Cancer,” released today in The New England Journal of Medicine (NEJM) for its October 24, 2013 issue. This study corroborates the increased IMRT treatment rates among self-referrers reported in the Government Accountability Office’s (GAO) August 2013 report, “Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny.”

Authored by Jean M. Mitchell, PhD, economist and professor at the McCourt School of Public Policy at Georgetown University, the NEJM manuscript provides an intricate analysis of treatment patterns by urologists before and after they acquired ownership of IMRT services, compared to the treatment patterns of non-self-referring urologists and urologists who practice at National Comprehensive Cancer Network® (NCCN®)-designated cancer centers (also non-self-referrers).

ASTRO Chairman Colleen A.F. Lawton, MD, FASTRO, voiced the Society’s grave concerns regarding this study’s results, “Dr. Mitchell’s study provides clear, indisputable evidence that many men are receiving unnecessary radiation therapy for their prostate cancer due to self-referral. While I am a prostate cancer specialist impassioned to eradicating the disease, I am equally dedicated to utilizing these powerful technologies prudently and in the best interest of each individual patient. We must end physician self-referral for radiation therapy and protect patients from this type of abuse.”

The two cohorts for the NEJM study data, obtained through Medicare claims from January 1, 2005 through December 31, 2010, include Medicare patients in 26 geographically dispersed states who were 1) treated at 35 self-referring urology groups in private practice matched to a control group of 35 non-self-referring urology groups in private practice, for a total of 38,765 patients; and 2) treated by 11 self-referring urology groups in private practice within close proximity to and matched directly to non-self-referring urologists at 11 NCCN® centers, for a total of 6,713 patients. Patient records were followed for a period of six months from the initial prostate cancer diagnosis to track treatment choices. Sixty percent of the self-referring urologists established their IMRT services during the period from January 1, 2008 through January 15, 2010.

A difference-in-differences analysis was used to isolate the impact of self-referral on changes of IMRT utilization over time, according to self-referral status. This approach controls for initial differences in practice patterns during the pre-ownership period as well as secular trends that affect the use of IMRT and are unrelated to ownership status. The analysis found that:

  • IMRT utilization among self-referring groups increased from 13.1 percent to 32.3 percent once they became self-referrers, an increase of 19.2 percentage points (146 percent). In contrast, IMRT utilization by non-self-referring urologists who were peers practicing in the same community-based setting was virtually unchanged—with a modest increase of 1.3 percentage points. Therefore, the difference-in-differences analysis reveals that self-referral accounts for 93 percent of the growth in IMRT.
  • IMRT utilization among the subset of 11 self-referring urology practices near NCCN® centers increased from 9 percent to 42 percent, an increase of 33 percentage points (367 percent), from the pre-ownership to the ownership period, compared to an insignificant increase of 0.4 percentage points at the NCCN® centers.
  • In addition to increased IMRT utilization, the data demonstrate decreases in utilization of other effective, less expensive treatment options by self-referring urologists. For example, brachytherapy decreased by 14.9 percentage points to just 2.7 percent of patients receiving this treatment in self-referring urology practices. These results are in stark contrast to non-self-referring urologists, for whom the study reports “virtually no change in practice patterns.”

The NEJM report concludes that “men treated by self-referring urologists, as compared with men treated by non-self-referring urologists, are much more likely to undergo IMRT, a treatment with a high reimbursement rate, rather than less expensive options, despite evidence that all treatments yield similar outcomes.”

At a press conference unveiling the study tomorrow, one of the nation’s leading urologists, James L. Mohler, MD, of Roswell Park Cancer Institute in Buffalo, will release a joint statement on the overtreatment of prostate cancer and physician self-referral from the expert members of the NCCN® Prostate Cancer Guidelines Panel, which he chairs.

“We are concerned unanimously by the prostate cancer treatment patterns identified in today’s article,” says Dr. Mohler. “We are disappointed to learn that urologists who self-refer for IMRT services use this expensive technology more than urologists who don’t self-refer and more than NCCN® Member Institutions.” He added, “Prostate cancer treatment recommendations should be based on the best available clinical evidence and not influenced by business or personal interests of the care provider.”

“This study confirms that permitting physicians to self-refer, particularly urologists to self-refer for IMRT, leads to unnecessary treatment and added health care costs to Medicare and beneficiaries,” continued Dr. Lawton. “Prostate cancer is a complicated disease that needs input from multiple specialists, not just one, to determine the best treatment for the individual patient. There are many different treatments available, and in many cases, no treatment at all is the right thing to do, particularly among the elderly. For many men with early stage prostate cancer, active surveillance, or watchful waiting, is the best option. Unfortunately, the continuous stream of data indicates that patient choice is being restricted—patients are being steered to the treatment that provides the most profit for the urologist. As a result, patients are subjected to unnecessary treatment and side effects, and millions of dollars are wasted.”

The federal “Ethics in Patient Referrals Act,” also known as the self-referral law, prohibits physicians from referring a patient to a medical facility in which he or she has a financial interest in order to ensure that medical decisions are made in the best interest of the patient without consideration of any financial gain that could be realized by the treating physician. However, the law includes an exception that allows physicians to self-refer for so-called “ancillary services,” including radiation therapy. Over the years, abuse of the in-office ancillary services (IOAS) exception has weakened the self-referral law and diminished its policy objectives, making it simple for physicians to avoid the law’s prohibitions by structuring arrangements that meet the technical requirements of the law, thereby circumventing the intent of the law. Numerous studies have shown that physician self-referral leads to increased utilization of services that may not be medically necessary, poses a potential risk of harm to patients and costs the health care system millions of dollars each year.

To-date, the GAO has issued three reports in a four-part series on physician self-referral, the most recent one, from August 2013, also details abuse in radiation therapy treatment for prostate cancer. The report found a 356 percent increase in IMRT utilization by self-referrers, compared to a 5 percent decrease by non-self-referrers, and that the number of treatments rose by 509 percent compared to a 3.8 percent decrease at non-self-referring multi-specialty groups. In July 2013, the GAO report, “Action Needed to Address Higher Use of Anatomic Pathology Services by Providers Who Self-Refer,” found that self-referring providers likely referred nearly one million more unnecessary anatomic pathology services than non-self-referring providers, costing Medicare approximately $69 million. “Higher Use of Advanced Imaging Services by Providers Who Self-Refer Costing Medicare Millions,” the first GAO report in November 2012 on self-referral in advanced diagnostic imaging, found that “providers who self-referred likely made 400,000 more referrals for advanced imaging services than they would have if they were not self-referring”—at a cost of more than $100 million in 2010. The final report, expected by the end of this year, will detail self-referral for physical therapy services.

“Unfortunately, when you look at the numbers in this report, you start to wonder where health care stops and where profiteering begins,” said Senate Finance Committee Chairman Max Baucus (D-Mont.), in a statement about the GAO’s August 2013 report on radiation therapy self-referral. “Enough is enough. Congress needs to close this loophole and fix the problem.”

“ASTRO urges Congress to promptly pass the ‘Promoting Integrity in Medicare Act of 2013′ (PIMA), introduced August 1, 2013, by Rep. Jackie Speier (D-Calif.) and Rep. Jim McDermott (D-Wash.). PIMA will close the self-referral loophole for radiation therapy, advanced imaging, anatomic pathology and physical therapy services, resulting in better care for patients and billions of Medicare dollars saved that could offset the costs of repealing the Medicare physician payment formula (sustainable growth rate—SGR).

“PIMA closes the self-referral loophole in a conscientious and strategic manner that abolishes abuse while allowing truly integrated multi-specialty groups and high-performing health systems to continue to provide high-quality and efficient care,” concluded Dr. Lawton. “This blatant abuse of our patient’s trust and our country’s limited financial resources endangers our ability to work with health policy leaders in developing a new quality- and value-based payment system for Medicare. Closing the self-referral loophole will protect patients, restore trust, reduce costs and strengthen Medicare.”

Reps. Speier’s and McDermott’s PIMA legislation would enact the recommendations of influential bipartisan groups who have examined self-referral abuse. In September 2012, a New England Journal of Medicine article, authored by leading health policy experts including former CMS administrator Donald Berwick, MD, MPP, called for closing the self-referral loophole for radiation therapy and other so-called “ancillary services.” The Center for American Progress agreed with narrowing the IOAS exception, as well as several notable bipartisan groups, including the Bipartisan Policy Center, under the leadership of former Senate Majority Leaders Tom Daschle (D-S.D.) and Bill Frist (R-Tenn.), and the Moment of Truth Project, headed by Erskine Bowles and former Senator Alan Simpson (R-Wyo.). President Obama’s proposed FY 2014 Budget also recommended closing the self-referral loophole and estimated savings of more than $6 billion during the standard 10-year budget window for Medicare.

A November 2012 Bloomberg News investigative report scrutinized questionable IMRT treatment for prostate cancer by a self-referring urology clinic in California and concluded that physician self-referral resulted in mistreated patients and higher health care costs. The Wall Street Journal, The Washington Post and The Baltimore Sun have published similarly critical reports since 2009 to call attention to the mounting evidence that limited specialty [urology] groups who own radiation therapy equipment have utilization rates that rise rapidly and are well above the national norms for radiation treatment of prostate cancer.

JM  Mitchell (2013). Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N. Engl. J. Med., 369:1629-1637 [Abstract]

Metformin for breast cancer less effective at higher glucose concentrations

A University of Colorado Cancer Center study published online this month in the journal Cell Cycle shows that breast cancer cell growth, motility and aggression is promoted by excess glucose, as experienced by patients with diabetes and metabolic syndrome. The study also showed that patients with high glucose may require higher doses of the drug metformin to achieve the same anti-cancer activity as patients with normal glucose levels.

Metformin, the most common first-line drug in the treatment of type-2 diabetes, has been shown in previous studies to reduce breast cancer risk, improve survival, and increase the effectiveness of chemotherapy. Numerous Phase III clinical trials are currently evaluating the benefits and best uses of metformin in breast cancer patients.

“We show that metformin works differently in high- compared to low-glucose conditions. Not only does it require a higher concentration of metformin to be active in high-glucose conditions, but we report that the drug regulates different genes within cancer cells at high as compared to normal glucose levels,” says Ann Thor, MD, CU Cancer Center investigator, Todd Professor of Pathology at the University of Colorado School of Medicine, and the study’s principal investigator.

The study evaluated the effects of metformin on 17 breast cancer cell lines representing each of the molecular subtypes of the disease, at varying glucose levels.

“Commonly, lab studies of metformin are performed with very high glucose concentrations – about 17 millimols of glucose per liter. But the average glucose level in healthy humans is only about one third of that dose – about 5 millimols per liter. And individuals with diabetes may have glucose at 10 millimols per liter. We wanted to study metformin activity under these conditions,” Thor says.

So the question was this: how would metformin perform in breast cancer cells grown at more realistic, human levels of glucose?

“Results show that when you drop glucose down to human levels, metformin has an even bigger effect at standard doses. When glucose is high you need more metformin to achieve the same results,” Thor says.

Thor also points out that skeptics of metformin treatment for cancer in general or breast cancer in particular frequently point to the high concentrations of metformin needed to create results in the laboratory.

“Our data helps to explain why higher doses of metformin are required to obtain anti-cancer effects when cancer cells are grown in the lab, as compared to its use in humans,” Thor says.

Interestingly, “it wasn’t simply that the metformin effectiveness went up as glucose came down, but that entirely new mechanisms of action were present at lower glucose levels,” Thor says.

Specifically, Thor and colleagues used RNA expression arrays to discover which genes were affected by metformin at high and low glucose concentrations. At high glucose concentrations, metformin primarily affected genes involved in metabolic processes and cell proliferation; at low glucose concentrations, metformin affected genes controlling cellular process and programmed cell death.

In addition to affecting the growth of breast cancer cells, Thor and colleagues show the drug decreases the ability of breast cancer cells to move within the body – a task necessary for the spread of the disease to other sites.

“An extension of this data implies that in breast cancer patients with diabetes or metabolic syndrome, metformin may less effective at the standard dose. To be effective, doctors may have to first explore glucose control or may have to use a higher dose of metformin,” Thor says.

Wahdan-Alaswad et al., (2013). Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle12 [Abstract]