Everolimus in Elderly Hormone-Receptor—Positive Breast Cancer Patients

	I read with great interest the article entitled “Breast Cancer: Will Treatment Costs Outpace Effectiveness?” by MP Zimmerman et al, published in the December 2012 issue (Volume 18, Special Issue 5, SP200-SP202) of 

. In response to the authors’ discussion regarding the potential for treatment costs to outpace effectiveness in breast cancer, I would like to provide clarification, specifically with respect to the effectiveness of everolimus combined with exemestane to treat patients older than 65 years.

	The authors accurately reported the overall results from BOLERO-2, a phase III trial (N = 724) with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in postmenopausal women with hormone receptor—positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) that was refractory to nonsteroidal aromatase inhibitors (NSAIs). Results of this trial show that treatment with everolimus plus exemestane improved progression- free survival (PFS) by 4.6 months, from 3.2 months with exemestane alone to 7.8 months with the combination therapy (local assessment, hazard ratio: 0.45; 95% CI: 0.38-0.54; P <0.0001).

 Although overall survival at the time of interim analysis was not mature, results at the median 18-month follow- up assessment showed that fewer deaths occurred among patients treated with everolimus plus exemestane compared with those treated with exemestane alone (25.4% vs 32.2%).

	Exploratory subgroup analysis of the BOLERO-2 trial at a median 18-month follow-up visit showed that for patients younger than 65 years and patients 65 years and older, improvements in PFS, overall response rate (ORR), and clinical benefit rate (CBR) were observed with everolimus + exemestane versus placebo + exemestane (

 Additionally for patients younger than 70

	years and 70 years and older, improvements in PFS ORR and CBR were observed with everolimus + exemestane versus placebo + exemestane (

). The safety profile of EVE + EXE in elderly patients with advanced BC was consistent with the known overall profile of each agent.

	In conclusion, contrary to the claim put forth by Zimmerman et al, results from the BOLERO-2 trial show that patients younger than 65 years and those 65 years and older with HR+ HER2— BC

	have the potential to benefit from treatment with everolimus + exemestane. Currently, everolimus, in combination with exemestane, remains the only mTOR inhibitor approved by the FDA for managing patients with HR+ HER2—BC that is refractory to NSAI therapy.

		Thank you for your somewhat belated comments on our article, “Breast Cancer: Will Treatment Costs Outpace Effectiveness?”, published in the December 2012 issue (Volume 18, Special Issue 5, SP200-SP202) of 

. The information presented in the article from the BOLERO-2 study was acquired from information cited in the abstract by Martine J. Piccart-Gebhart, et al, presented at the June 2012 American Society of Clinical Oncology meeting and the press release from the FDA on July 23, 2012, announcing that it had approved everolimus.

 The information available at the time showed that everolimus had an overall positive effect when used in combination therapy for breast cancer. These 2 references did not contain any efficacy results stratified by age.

		Additional subgroup analysis is quite often performed after initial results of trials are presented. These subgroup analyses many times identify efficacy and safety information that is valuable to clinicians in treating and managing their patients. Thank you for providing further valuable information that will assist clinicians in determining optimal therapy for their patients.

Data discussed in this letter were presented at the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL (Abstracts 551 and 559); and at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX (Poster P6-04-02). Everolimus in Elderly Hormone- Receptor—Positive Breast Cancer Patients.

 Dr Rogerio reports employment with Novartis Pharmaceuticals Corporation, which funded this study.

 Concept and design; acquisition of data; critical revision of the manuscript for important intellectual content.

 Jaqueline Rogerio, MD, Senior Medical Director, Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ 07936. E-mail: jaqueline .rogerio@novartis.com.

	1. Piccart M, Baselga J, Noguchi S et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX.

	2. Pritchard KI, Burris HA, Rugo HS et al. Safety of everolimus for women over 65 years of age with advanced breast cancer (BC): 18-month follow-up of BOLERO-2 2012. Presented at the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL.

		3. Piccart-Gebhart MJ, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. 

		4. Drugs: everolimus. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm313008.htm. Published July 23, 2012. Accessed September 12, 2012.

Articles

Evidence-Based Oncology

Everolimus in Elderly Hormone-Receptor-Positive Advanced Breast Cancer Patients

Stem cell therapy has gained increasing traction in various therapeutic areas, from cancer to diabetes to ocular regeneration. Although the use of embryonic stem cells is controversial, remarkable research in the field of adult induced pluripotent stem cells (iPSCs) has highlighted the tremendous potential of this unique treatment in development and regeneration. Additionally, understanding how stem cells function would improve our insight into various diseases—to fathom “what went wrong.”

Globally, patients are actively being recruited to participate in clinical trials of these regenerative therapies. A biotechnology company, Advanced Cell Technology, is testing human embryonic stem cell (hESC)-derived retinal cells for 2 different eye diseases: Stargardt’s macular dystrophy,

 which is a form of juvenile macular degeneration, and age-related macular degeneration.

 These are primarily phase 1 and 2 safety and efficacy trials, and a preliminary report published in early 2012 did not observe any safety issues with the therapy.

 Hematopoietic stem cells (HSCs), isolated from the bone marrow or umbilical cord blood, have been widely used to treat blood cancers and other blood disorders for a while now. Osiris Therapeutics, based out of Columbia, Maryland, is currently conducting phase 2 trials using human mesenchymal stem cells (MSCs) to repair heart tissue following a heart attack, repair lung tissue in chronic obstructive pulmonary disease patients, and protect pancreatic beta cells in patients with newly diagnosed type 1 diabetes mellitus.

While bone marrow transplants for numerous blood disorders, including cancer, have been covered by insurance policies for some time now, stem cell therapies are increasingly gaining attention with improved and less ethically challenging procedures being developed from adult stem cells.

Stem cells, during early stages of development (in infants and children), have the unique potential to develop into any cell type, a property defined as “pluripotency”. Additionally, stem cells, even in adults, have “regenerative” potential, which helps them replenish damaged tissues and organs. These cells present distinct behavior depending on their site or location in the body, and they respondrespond to specific environmental cues. For example, stem cells in the gut and HSCs regularly divide to repair and replenish worn-out tissues, while stem cells in organs like the pancreas or the heart divide only under specific conditions.

Distinct from other cell types, stem cells have the ability to undergo cell division and replicate, even after dormancy. Additionally, following specific cues, they can be prompted to differentiate into tissue- or organ-specific cells with special functions.

 Although every human organ (except nerve cells) can undergo repair by stem cells, the process dwindles with age, or is quite inactive in some organs and tissues.

 Most of the current research, independent of the therapeutic area, is geared toward understanding the stimuli that activate/reactivate stem cells to allow for age- or disease-related tissue damage.

The human body is primarily the source of 2 types of stem cells:

. hESCs are derived from embryos that remain unused following in vitro fertilization, following the informed consent of the donor.

 These cells need specific signals to differentiate to the required cell type, but they run the risk of developing into a tumor if injected directly.

 Thus, in addition to the associated ethical issues, tumor formation and transplant rejection are some of the barriers faced with hESCs.

The use of adult stem cells, such as HSCs, does not involve any ethical issues, and when obtained from the recipient, the cells are not susceptible to immune rejection. An adult stem cell—an undifferentiated cell that exists among differentiated cells in a tissue or organ&mdash;is capable of generating the cell types of the tissue in which it resides, and maybe unipotent or multipotent. The field is burgeoning, and there is tremendous excitement among researchers to use adult stem cells in therapy. While HSCs have long been used in stem cell transplants, MSCs (non-HSCs) can generate cartilage, bone, and fat cells to form blood and fibrous connective tissue (

Exciting, albeit controversial, results of human cloning were recently published in the journal 

 following collaborative research conducted by scientists at the CHA Stem Cell Institute in Seoul, Korea, the Research Institute for Stem Cell Research (a part of the CHA Health Systems), and the company Advanced Cell Technology. The scientists “reprogrammed” an egg cell by removing its DNA and replacing it with nuclei from 2 adult donors aged 35 years and 75 years. The experimental procedures could successfully generate 2 karyotypically normal diploid ESC lines. This technique had previously been developed, but with infant/fetal donor cells, which, unlike adult cells, are not associated with agerelated changes such as shortened telomerases and oxidative DNA damage.

Extracting and then maintaining adult stem cells in the laboratory is extremely difficult, as they have a limited capacity to divide in culture.

 The discovery of the “transdifferentiation” process of adult stem cells, wherein adult stem cells are subjected to certain differentiation techniques to generate cell types different from the predicted types, was therefore very exciting.

 Taking the process a step further, researchers in Japan developed a technique to reprogram normal adult cells into stem cells, called induced pluripotent stem cells (iPSCs), by the forced introduction of a set of transcription factors into the cells.

 These transcription factors (different combinations of Oct4, Sox2, Klf4, c-Myc, Nanog, Lin28) regulate important steps in early embryonic development and force the adult somatic cells into an embryonic stem cell—like state. This technique has essentially revolutionized the field of regenerative medicine; the patient himself could now be an unlimited source of immune-matched pluripotent cells.

As promising as the therapy sounds, it is riddled with its own problems. It has always been known that the genes that regulate developmental pathways also regulate cancer, and are especially potent when expressed in combination. Therefore, researchers have trimmed the initial group of 4 transcription factors down to 2, with the aim of simultaneously treating the cells with various chemicals to boost reprograming efficiency. Additionally,the use of either lentiviruses or retroviruses (

) to introduce the genes into the host cell can result in uncontrolled effects of viral integration. Current efforts are directed toward reprograming cells without viruses or using more efficient integration techniques.

iPSCs offer tremendous potential in understanding disease, developing drug candidates, and regenerative medicine. Disease-specific iPSCs are being developed to treat Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, diabetes, and ALS/Lou Gehrig’s disease.

Researchers at the RIKEN Center for Developmental Biology in Japan have piloted the first set of studies to evaluate iPSCs in humans. In August 2013, patient recruitment was initiated to evaluate the safety and efficacy of iPSC-derived retinal pigment epithelium (RPE) cells in patients with agerelated macular degeneration.

The premise for using iPSCs is the fact that the current remedies for the disease prevent further damage without promoting any repair.

A new iPSC transplantation therapy will also be evaluated for safety in patients with Parkinson’s disease. Jun Takahashi, MD, PhD, and his colleagues at the Kyoto University’s Center for iPS Cell Research and Application have successfully developed a technique to generate dopamine-producing nerve cells from patient-derived iPSCs for transplantation into the patient’s brain, an attempt at regenerating the damaged dopaminergic neurons.

 When contacted by e-mail, Takahashi responded that they are currently conducting preclinical studies, the results from which will be submitted for approval prior to initiating clinical trials.

In a novel approach, researchers at the RIKEN Research Center for Allergy and Immunology reported the generation of cancer-specific killer T cells from iPSCs. The human body has a natural ability to produce tumor-specific cytotoxic T lymphocytes, which when activated are effective but not sufficient to cure the patient, due to their short lifespan. To tackle this problem, the scientists reprogrammed T cells into iPSCs, which were further manipulated to differentiate into mature T cells. Although the tools are ready, they have not yet been tested in vitro or in vivo for their cancer cell—killing potential.

The concept of a cancer stem cell (CSC) has been around for quite some time; scientists found it easier to explain the problems of resistance, recurrence, and minimal residual disease in cancer by acknowledging that these types of cells do exist.

A CSC is defined by its ability to regenerate an entire tumor and is explained by either a stochastic model (every cancer cell can become a CSC) or the hierarchical model (which identifies CSCs as an independent entity within a tumor).

 Recently, the dynamic CSC model has been gaining hold, which proposes that the differentiated cancer cells can reacquire CSC features following environmental cues (

 Either way, the persistent problem faced in cancer treatment is the elimination of these cells. The cells that survive gather mutations as they evolve, especially after exposure to drugs, and develop increasing resistance. Additionally, the entire region becomes more fluid—creating a stem cell “niche”&mdash;due to crosstalk with the tumor microenvironment that further promotes tumor maintenance.

When asked to comment on the importance of CSCs in malignancy and resistance, Robert Weinberg, PhD, Daniel K. Ludwig Professor for Cancer Research in the Department of Biology at the Massachusetts Institute of Technology and a founding member of the Whitehead Institute for Biomedical Research, said in an e-mail, “There is increasing evidence that carcinoma cells that have undergone an epithelial-mesenchymal transition (EMT) are more aggressive clinically, sources of metastasis, and poised to enter into the CSC state, which by definition confers on them tumor-initiating powers. Presumably such powers are critical for disseminated cancer cells to serve as the founders of new metastatic colonies. Moreover, CSCs appear to be generally more resistant to a variety of currently employed chemotherapeutics, making them sources of residual disease following initial treatment in the oncology clinic and thus sources of clinical relapse.”

In response to whether he thought that the stromal cells that constitute the tumor milieu might be differentiated CSCs that feed back and promote the aggressiveness of the disease, Weinberg, who also serves as the chairperson on the scientific advisory board of the biopharmaceutical company Verastem, said, “Since carcinoma cells that have undergone EMT take on many of the attributes of the mesenchymal cells in the adjacent recruited host stroma, they may take on many of the attributes of naturally arising stromal cells; however it remains unclear whether these mesenchymally converted carcinoma cells contribute significantly to the overall cellularity of the stroma.”

Interfering with the innate survival signals in CSCs, as well as the survival signals that are transmitted to CSCs from the tumor environment, seems the most likely path to follow to eliminate these culprits. This approach has proved to work in preclinical animal models and is being applied to humans as well. Companies such as Verastem, Stemline, and OncoMed are developing drugs that would specifically target the CSC population in various tumors (

Is regenerative medicine covered? Payers such as Humana, Blue Cross and Blue Shield, Aetna, and UnitedHealth definitely have policies in place for HSC and bone marrow transplants, a procedure that has been in use for a long time now for patients with blood disorders. However, companies that have developed, or are in the process of developing, regenerative therapies, face hurdles with not just the FDA, but also reimbursement.

The company Advanced BioHealing developed 

, a product that consists of allogenic human fibroblasts, to aid with wound closures in diabetic foot ulcers. In 2011, the company was acquired by Shire Pharmaceuticals, which immediately initiated the task of improving the reimbursement profile for 

and put 2 new procedure codes in place for the product.

, an autologous dendritic cell therapy manufactured by Dendreon for the treatment of advanced prostate cancer, also faced stumbling blocks, initially for FDA approval. Subsequently, the CMS did not provide an automatic coverage for this expensive treatment ($93,000 for 3 doses) following the approval, but rather reviewed the payment process first before approving it after a year. Medicare coverage was absolutely essential for this drug, since 75% of the target population was Medicare eligible (65 years or older). Thus the combination of the price and the large number of patients that would be eligible for this treatment was the premise for Medicare’s extended review.

According to a brief released by the Alliance for Regenerative Medicine, an advocacy organization that creates a common platform for commercial, academic, and not-for-profit institutions, Medicare requires that the regenerative therapy should fall within a defined Medicare benefit and the parameters of one of these segments to qualify for payment. Medicaid relies more on managed care and strict formularies, while private health plans may primarily be concerned with whether the therapy falls under the medical benefit or prescription drug benefit. FDA approval is necessary but no longer sufficient for reimbursement.

Defining the bottom line for the highcost coverage of regenerative medicine requires answering the same question that must be asked in considering expensive treatments such as Sovaldi and Olysio (hepatitis C). Although the upfront cost of treatment is very high, if the therapy proves to have 

effects, it could help avoid long-term treatment costs, especially for chronic conditions. In order for insurance companies to cover these therapies, stem cell therapy would need to prove a substantial advantage over preexisting and relatively inexpensive treatment options. 

	1. Sub-retinal transplantation of hESC derived RPE (MA09-hRPE) cells in patients with Stargardts macular dystrophy. ClinicalTrials.gov website. http://www.clinicaltrials.gov/ct2/show/ NCT01345006?term=ACT+and+human+embryo nic&rank=1. Accessed April 4, 2014.

	2. Safety and tolerability of sub-retinal transplantation of hESC derived RPE (MA09-hRPE) cells in patients with advanced dry age related macular degeneration (Dry AMD). ClinicalTrials.gov website. http://www.clinicaltrials.gov/ct2/show/ NCT01344993?term=ACT+and+human+embryonic&rank=2. Accessed April 4, 2014.

	3. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. 

	4. Stem cells and diseases. National Institutes of Health website. http://stemcells.nih.gov/info/ pages/health.aspx. Accessed April 4, 2014.

	5. Stem cell basics. National Institutes of Health website. http://stemcells.nih.gov/info/basics/Pages/Default.aspx. Accessed April 3, 2014.

	6. Stem cells and cancer. Ludwig Center for Cancer Stem Cell Research and Medicine website. http://ludwigcenter.stanford.edu/overview/. Accessed April 14, 2014.

	7. Types of stem cells. GE Healthcare Life Sciences website. http://www.gelifesciences.com/webapp/wcs/stores/servlet/catalog/en/GELifeSciences-us/applications/types-of-stemcells/. Accessed April 14, 2014.

	8. Cha HJ, Hwang ES. Current status of biology, bioengineering, and therapeutic potential of stem cells. 

	9. Chung YG, Eum JH, Lee JE, et al. Human somatic cell nuclear transfer using adult cells [published online April 17, 2014]. 

. doi:http://dx.doi.org/10.1016/j.stem.2014.03.015.

	10. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. 

	11. Regenerative medicine. Department of Health and Human Services. http://stemcells.nih.gov/info/scireport/Pages/2006report.aspx. Published August 2006. Accessed April 4, 2014.

	12. Pilot clinical study into iPS cell therapy for eye disease starts in Japan [press release]. RIKEN; July 30, 2013. http://www.riken.jp/en/pr/press/2013/20130730_1/. Accessed April 4, 2013.

	13. Geji K. Scientists to test iPS cells for Parkinson’s disease therapy. 

. http://ajw.asahi.com/article/behind_news/social_affairs/AJ201306070062. Published June 7, 2013. Accessed April 15, 2013.

	14. Vizcardo R, Masuda K, Yamada D, et al. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. 

	15. Filipovic A, Stebbing J, Giamas G. Cancer stem cells—therapeutic targeting or therapy? 

	16. Vermeulen L, de Sousa e Melo F, Richel DJ, Medema JP. The developing cancer stem-cell model: clinical challenges and opportunities. 

	17. Schaffer C, Littman N. Why planning your payment strategy is critical in early product development. California Institute for Regenerative Medicine website. http://cirmresearch. blogspot.com/2013/06/cirm-webinar-whyplanning-your-payment.html. Published June 17, 2013. Accessed April 17, 2014.

	18. Larkin C. Dendreon wins final Medicare coverage decision on prostate cancer drug. Bloomberg website. http://www.bloomberg.com/news/2011-06-30/dendreon-wins-finalmedicare- coverage-decision-on-prostate-cancerdrug. html. Published June 30, 2011. Accessed April 17, 2014.

	19. Maziarz R, Driscoll D. Hematopoietic stem cell transplantation and implications for cell therapy reimbursement. 

	20. Alliance for Regenerative Medicine. Alliance for Regenerative Medicine reimbursement portfolio. http://www.cirm.ca.gov/sites/default/files/files/agenda/ARM_Reimbursement_Portfolio_ Oct_2013_0.pdf. Accessed April 17, 2014.

Stem Cells Create a Therapeutic Niche

The statistics related to the negative health and financial impacts of tobacco use have been cited numerous times, but they remain staggering each time you see them:

• 42 million people in the United States continue to smoke and 16 million current and former smokers have smoking-related illnesses

• More than 480,000 deaths occur each year in the United States as a result of smoking

• Tobacco use costs $132 billion in direct medical costs and $157 billion in lost productivity.

What these numbers make abundantly clear is that, despite 4 decades of concerted tobacco control efforts, finding ways to reduce the morbidity and mortality associated with tobacco use is

one of the most important public health challenges we face as a nation.

On February 5, 2014, CVS Caremark announced that our company will stop selling cigarettes and other tobacco products at all CVS/pharmacy stores across the country—that’s more than

As the first national pharmacy chain to make such a commitment, we came to this decision because we believe the sale of tobacco products in our stores poses a paradox that is at odds with our role as a healthcare company and contradicts our purpose of helping people on their path to better health.

Over the past 40 years, a variety of policies have helped reduce the prevalence of cigarette smoking, including increases in tobacco taxation, legislation to create smoke-free public areas, and

In 1965, 43% of US adults smoked cigarettes, compared with 18% of US adults today.

 Despite this progress, in the past decade the rate of reduction in smoking prevalence has stalled, suggesting that new approaches and interventions are needed.

Recently, public health advocates have been turning toward programs designed to make smoking less socially acceptable. The rationale for this approach is that increasing the stigma of tobacco use and reducing the social acceptability associated with smoking could result in fewer people smoking and an increase in the number of smokers who attempt to quit. One example of this approach includes the launch of 3 large-scale, national, mass media campaigns in 2014 by the CDC, the FDA, and the Legacy Foundation for Health. Another example is the ban on smoking in outdoor public spaces in New York City.

Studies have also demonstrated a clear relationship between tobacco use and the geographic density of stores that sell cigarettes.

 This research supports the concept that access to cigarettes can play a role in reducing tobacco use. At CVS Caremark we believe that combining reduced access to cigarettes with policy changes at the state and federal level, and efforts to make tobacco use less socially acceptable, could help further reduce tobacco use and its resulting negative health and financial consequences.

For CVS Caremark, removing cigarettes and other tobacco products from our CVS/pharmacy locations is a concrete way we can help reduce access and make these products less readily

available. As a company of 26,000 pharmacists, nurse practitioners, and physician assistants who provide trusted advice to 5 million customers each day, selling tobacco products contradicts our core commitment to healthcare and our growing role as an integral part of the healthcare system.

As pharmacies are becoming more and more involved in chronic disease management and counseling, we find ourselves faced with a conundrum. How can we provide support and counseling to patients who have high blood pressure, high cholesterol, and diabetes—all conditions that are exacerbated by smoking&mdash;and then turn around and sell them cigarettes?

Clearly, tobacco products have no place in a setting where healthcare is delivered. When we think about where we expect to be in the future as a healthcare company, it is clear that removing

tobacco products from our stores is the right thing to do.

CVS Caremark is not alone in recognizing the paradox of selling cigarettes and tobacco products at pharmacies that are supposed to be focused on healthcare. Back in 2010, the American

Pharmacists Association urged pharmacies to discontinue the sale of tobacco products and urged state pharmacy boards to stop issuing and renewing licenses for pharmacies that sell these

 The American Medical Association has passed a resolution opposing the sale of tobacco products in pharmacies, and calls to ban tobacco sales in pharmacies have also

come from the American Heart Association, the American Cancer Society, and the American Lung Association (ALA). Even cities in California and Massachusetts, particularly San Francisco and

Boston, have banned the sale of tobacco products in pharmacies,

 and efforts to institute statewide prohibitions are on.

Our decision to stop selling tobacco products at CVS pharmacy locations may not cause the majority of people to stop smoking; smokers will most likely simply go somewhere else to buy their cigarettes. But if other retailers that are focused on healthcare recognize this paradox and follow our lead, tobacco products will become much more difficult to obtain. And, perhaps this will reinforce the social unacceptability of tobacco use, as people begin to realize that pharmacies no longer sell tobacco products because it is not conducive to the promotion of health and well-being that these institutions stand for.

We think this concept is catching on. Shortly after we made our announcement, 8 senators—led by Senate Health, Education, Labor and Pensions Committee Chairman Tom Harkin (D-IA)&mdash;sent a letter to the CEOs of Rite-Aid, Walgreens, and the National Association of Chain Drug Stores (NACDS) urging them to follow our example. In the letter, the senators said, “By reducing the availability of cigarettes and other tobacco products and increasing access to tobacco cessation products, [you, as a company,] have the power to further foster the health

and wellness of [your] customers and send a critical message to all Americans—and especially children&mdash;about the dangers of tobacco use.”

In addition, a few weeks later, 26 of the nation’s leading public health and medical organizations—ranging from the American Academy of Pediatrics to the American Public Health Association&mdash;issued an open letter citing our decision and calling on other drugstores and retailers to also end the sale of tobacco products. These actions reinforce the odd juxtaposition inherent in selling tobacco products in a retail location that promotes health and wellness, and recognize the potential impact of reducing easy access to tobacco products.

Although surveys show that 7 out of 10 smokers say they want to quit, we do recognize that quitting smoking is not an easy task. As a result, in tandem with our decision to stop selling tobacco

products, CVS Caremark is also making a pledge to actively help Americans quit smoking. This spring we will launch a robust national smoking cessation program that will encompass the assets of our full enterprise as a retail pharmacy, retail clinic provider, and pharmacy benefit manager, because research shows that quitting smoking has proven health benefits.

According to the ALA, as soon as 12 hours after quitting smoking, carbon monoxide level in the bloodstream returns to normal; 2 to 3 months after quitting, the risk of heart attack begins to drop and lung function begins to improve; 1 year after quitting, the added risk of coronary heart disease is half that of a smoker; and 5 to 15 years after quitting, the risk of stroke is reduced to that of a nonsmoker.

Our goal is to reduce easy access to cigarettes, help those people who want to quit smoking do so, and help people along their path to better health.

1. The Health Consequences of Smoking: 50 Years of Progress. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.

2. Frieden TR. Tobacco control progress and potential. JAMA. 2014;311(2):133-134.

3. Pearce J, Hiscock R, Moon G, Barnett R. The neighourhood effects of geographical access to tobacco retailers on individual smoking behaviour. J Epidemiol Community Health. 2009;63(1):69-77.

4. American Pharmacists Association. Report of the 2010 APhA House of Delegates: discontinuation of the sale of tobacco products in pharmacies and facilities that include pharmacies. J Am Pharm Assoc. 2010;50(4):471.

5. Katz MH. Banning tobacco sales in pharmacies: the right prescription. JAMA. 2008;300(12):1451-1453.

6. American Lung Association. Benefits of Quitting. http://www.lung.org/stop-smoking/how-toquit/why-quit/benefits-of-quitting/.

CVS Caremark Quits for Good: Our Decision to Stop Selling Tobacco Products

Cancer. When we first think of the disease, genetics and environmental factors spring to mind. However, obesity, the other epidemic that faces the United States, has also been associated with an increased risk of numerous cancers (

). A National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data study classified 4% of new cancer cases in men and 7% in women in 2007 to be a result of obesity.

Although the actual percentages of cases varied for different cancers, endometrial and esophageal cancers had the highest numbers. According to the study, even a small reduction (1%) in the body mass index (BMI) of every adult could reduce the incidence of new cancer cases by about 100,000.

 Interestingly, although associated with an increased risk of developing such malignancies as colorectal cancer, esophageal adenocarcinoma, cancers of the gallbladder, pancreas, liver, kidney, and thyroid, non-Hodgkin lymphoma, multiple myeloma, ovarian cancer, and prostate cancer, the development of a few cancers including lung cancer, premenopausal breast cancer, and esophageal squamous cell carcinoma have been inversely associated with obesity.

Not only are obese patients at an increased risk of developing malignancies, they have also been found to be at a significantly greater risk of dying due to the malignancy. A prospective study published back in 2003 on a large cohort (more than 900,000 adults) demonstrated that among heavy patients, with a BMI of at least 40 kg/m

, death from cancer was 52% higher among men and 62% higher among women compared with their corresponding “normalweight” controls. These results, determined based on a 16-year follow-up period, identified the cancers carrying the highest risk of obesity-associated cancer death as liver and pancreatic cancer in men and uterine, kidney, and cervical cancer in women.

Two studies that drive in the nail on the link between obesity and cancer were conducted in Sweden and in the United States. The Swedish prospective study evaluated the outcomes of bariatric surgery in 2010 patients compared with 2036 controls, after a median follow-up of 10.9 years, and identified a 40% reduction in cancer incidence.

 A retrospective study conducted in a single clinic in Utah that compared 7925 patients who had undergone bariatric surgery with 7925 matched controls during a follow-up period of 7.1 years revealed a 60% decrease in cancer mortality associated with bariatric surgery.

Acknowledging the rise in evidence for obesity as a risk factor for cancer and other diseases, payers have recognized that a healthy body weight can reduce the incidence and complications of various diseases, which in turn would reduce medical costs and improve productivity. Mechanism of the Increased Risk Research delving into the molecular basis for the increased association of obesity with cancer risks has provided several leads. These include molecules such as estrogen, insulin, insulin-like growth factor-1, and adipokines (

). Additionally, chronic low-level inflammation, oxidative stress, and altered microbiomes are risk factors for cancer observed in obese individuals.

Overweight and obese women who have not been exposed to hormone therapy develop a modest risk of postmenopausal breast cancer for estrogen and progesterone receptor—expressing tumors due to an increased level of estrogen production, but are at a reduced risk of premenopausal breast cancer. Following menopause, the ovaries stop estrogen production and the fat tissue becomes the primary source of the hormone. Obese women, with more fat tissue, have higher estrogen levels, resulting in a rapid growth of estrogenresponsive tumors.

A study recently presented by researchers from the German Breast Group, Neu-Isenburg, Germany, at the 9th European Breast Cancer Conference held in Glasgow, Scotland, reported that a high BMI is an adverse determinant of survival without recurrence or metastasis. However, the study, conducted in 11,000 patients with early breast cancer treated with neoadjuvant therapy, reported that HER2-positive patients did not have obesity as a risk factor. Another issue raised by the study is that obese patients were observed to have received a lower dose of chemotherapy due to a dose cap resulting from a fear of overdosing.

But this could result in a lower quality of chemotherapy in that population, which could stem a relapse.

 At the molecular level, a link between high caloric intake and altered breast cancer gene 1 (BRCA1) transcription has been discovered. BRCA1 plays a very important role in DNA repair, cell cycle regulation, and transcriptional regulation, and mutations or altered expression of the protein have been shown to be detrimental to the cell, leading to increased proliferation, chromosomal instability, and tumorigenesis. The transcriptional corepressor C-terminal—binding proteins (CtBP1 and CtBP2) are a part of the transcriptional machinery that binds to the BRCA1 promoter and represses expression of the gene. High caloric intake and obesity were found to disrupt the NAD+/NADH ratio, resulting in increased CtBP activity and subsequently a reduced expression of BRCA1.

Studies conducted in Europe have identified obesity as the root cause of 11% of colorectal cancer cases. Obese men seem particularly at risk, with studies showing that obesity is associated with a 30% to 70% increased risk of colon cancer in men.

 A high dietary glycemic load, a known risk factor for obesity, was found to be significantly associated with an increased risk of recurrence and mortality in stage 3 colon cancer patients.

 The prospective, observational study was conducted in 1011 stage 3 colon cancer patients receiving adjuvant chemotherapy.

The patients reported their dietary consumption during, and 6 months after, participation in the chemotherapy trial, and the impact of their glycemic load, glycemic index, fructose, and carbohydrate intake on cancer recurrence and mortality was evaluated. Significantly, the increased risk of recurrence and death with higher dietary glycemic load and total carbohydrate was primarily observed in overweight and obese patients.

A recently published study in the journal Cell Metabolism, by scientists at the National Institute of Environmental Health Sciences, identified an important role of the gene NAG-1, known to protect against colon cancer, in preventing weight gain in mice fed a high-fat diet. The scientists generated mice that expressed human NAG-1, while the control mice did not. When fed the same high-fat diet, the NAG-1—expressing mice stayed lean while the controls grew plump. Further, cells isolated from the colon of the obese mice showed altered patterns of histone acetylation, a sign of cancer progression.

BMI has also been identified as a risk factor for pancreatic adenocarcinoma (PAC), the 13th-most common cancer and the 8th-leading cause of cancerrelated death in the world. Overweight or obese individuals were observed to have an increased risk of PAC, and an earlier age of onset. Further, overweight or obese older patients were also at an increased risk of dying due to the disease.

Genetic factors that regulate obesity have also been found associated with PAC. NR5A2 plays an important role in lipid and glucose metabolism, improving glucose uptake, and regulating cholesterol transport, and a significant association between NR5A2 gene variants and a decreased risk of pancreatic cancer has been identified.

Although Medicaid programs in most states and Medicare do not cover weight loss drugs,

 screening and counseling for obesity are covered by Medicare.

 Further, most private insurance companies will be forced to cover their patients’ weight loss efforts thanks to the Affordable Care Act.

Early this year, Aetna announced the launch of a program to assess the influence of weight loss and other lifestyle improvement tools to lower medical costs, improve health outcomes, and increase workplace productivity. The agenda includes a pilot program geared for self-insured plan sponsors to evaluate 2 FDA-approved (in 2012) prescription weight loss drugs, Belviq and Qsymia, among high-risk members. Results from this pilot are expected by the end of 2014.

When contacted for comment, Edmund Pezalla, MD, MPH, national medical director for pharmacy policy and strategy at Aetna, said in an e-mail response: “Yes, there are epidemiologic data to suggest that obesity increases the risk of cancer. We don’t know if treating obesity will reduce that risk (ie, by the time you treat, has something changed in the patient’s biology?).

We are not promising or counting on reducing cancer risk as a return on our program.” He went on to say, “Our program will not go on long enough or with enough patients to determine the reduction in risk from weight loss for many important factors, but from the existing literature we do expect to see some results:

• Short term: reduced use of medications and other improvements in the control of diabetes, high blood pressure, and cholesterol;

• Medium term: reduction in need for bariatric surgery and treatment of some other weight related disorders like gastroesophageal reflux; and

• Long term (and beyond the scope of our projects): reduction in patients progressing to diabetes, cardiac events, and other weight-related problems like need for joint replacement.”

Organizational Efforts to Combat Obesity as a Risk Factor for Cancer

The Obesity Society, based in Silver Spring, Maryland, is actively working at combating obesity, with the aim of confronting the associated comorbidities, including cancer. The society launched the Treat Obesity Seriously campaign last year to educate policy makers on the need to recognize obesity as a serious condition and provide clinicians with useful diagnostic tools.

 The society also serves as a platform to promote collaborations among members to boost cancer-obesity research at the molecular, clinical, and epidemiological levels, and to communicate the resulting information to professional and lay audiences.

This could prove an important step in obesity prevention efforts, especially with evidence of the associated disease risks in obese individuals, including but not limited to chronic conditions such as diabetes, cardiovascular disease, and cancer. Especially for cancer, improvements in research strategies, such as the development of biologicals, have seen a rapid increase in drug prices as well as the associated treatment costs (

). It’s a bubble that is rapidly expanding and could burst anytime.

With this realization, redirecting efforts to prevent disease onset and regulating the associated risk factors is of the essence.

1. Obesity and cancer risk (fact sheet). National Cancer Institute website. http://www.cancer.gov/cancertopics/factsheet/Risk/obesity. Accessed April 17, 2014.

2. Berger NA. Obesity and cancer pathogenesis. Ann NY Acad Sci. 2014;1311:57-76. 3. Calle EE, Rodriguez C, Walker-Thurmond W, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638.

4. Sjöström L1, Gummesson A, Sjöström CD, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10:653-662.

5. Adams TD, Gress RE, Smith SC, et al. Longterm mortality after gastric bypass surgery. N Engl J Med. 2007;357:753-761.

6. Obesity and diabetes have adverse effects on outcomes across different tumour types and should be taken into account when planning breast cancer treatment. European Cancer Organisation website. http://www.ecco-org.eu/Global/News/EBCC9-PR/2014/03/Fontanella-Obesity-and-diabetes-have-adverseeffects-on-outcomes-across-different-tumour.

aspx. Published March 20, 2014. Accessed April 15, 2014. 

The Double Whammy of the Obesity Epidemic: Increased Susceptibility to Cancer

A new paper diagnostic test for cancer? That is what engineers at the Massachusetts Institute of Technology (MIT) have developed—a simple, low-cost, noninvasive paper test that can improve diagnosis rates and hasten treatment.

The test, which essentially works like a pregnancy test, may have the potential to determine if a patient has cancer—within minutes.

Developed by Sangeeta Bhatia, MD, PhD, director of the laboratory for multiscale regenerative technologies at MIT, the technology is based on nanoparticles that interact with proteases (proteins, known to be overexpressed in numerous tumors, that can cleave peptide bonds), which can release hundreds of biomarkers that can be detected in the patient’s urine. Bhatia’s group designed nanoparticles conjugated to ligand-encoded reporters through protease-sensitive peptide substrates. The ligand on the nanoparticles is targeted to reach the disease site, be it solid tumors or blood clots or other sites, where upregulated proteases cleave the peptide substrates and release the reporters that are excreted in the urine. The urine can be tested either by a paper lateral flow assay or a sandwich enzyme-linked immunosorbent assay.

This diagnostic platform, claim the authors, can be applied in any disease setting without expensive equipment or trained medical personnel, and may allow low-cost diagnosis of disease at the point of care in resource-limited settings.

The novel aspect of Bhatia’s work is designing the exogenous nanoparticle biomarkers; companion point-of-care (POC) diagnostic paper strips were originally invented through a collaborative effort between researchers at Harvard University and the University of Sao Paulo. Driven by the need to develop easy-to-use diagnostics in the developing world, based on the World Health Organization’s ASSURED (affordable, sensitive, specific, user-friendly, rapid and robust, equipment free, and deliverable to end-users) criteria, the microfluidic paper-based analytical devices (mPADs) were developed as a new class of POC diagnostic.

Urinalysis assays using mPADs proved that the platform was ideal for ASSURED diagnostics.

Diagnostics For All (DFA), a company based in Cambridge, Massachusetts, has licensed out this patterned paper technology that was developed by the Harvard research group, with the aim of developing POC diagnostics for the developing world.

Currently, the company is working on the following diagnostic tests:

• Liver function tests (to monitor patients on antiretroviral therapies)

• Rapid immunity assessment (to monitor efficacy of vaccination against tetanus and measles; funded by the Bill and Melinda Gates Foundation)

• Child nutrition monitoring (funded by the Bill and Melinda Gates Foundation)

 that it is not currently developing any oncology diagnostic test.

paper describes using the platform to detect colorectal cancer and thrombosis, diseases associated with an abundance of active proteases, the applications are enormous. These studies were conducted in a mouse model; in order to guide the results to the next level and study patient populations, Bhatia aims to develop a business plan for a startup based on a Technological Innovation grant that the group received to commercialize the technology and conduct clinical trials.

The research group is also working on developing an implantable nanoparticle formulation that could aid long-term monitoring.

The engineering of low-cost and rapid assays to detect cancer has been on the rise. Mechanical engineers at the University of Washington, working in collaboration with a pathologist in the school of medicine, have developed a device that can help diagnose pancreatic cancer earlier and faster by avoiding the time-consuming manual labor associated with processing biopsy tissue samples. The microfluidic gadget (simply a modified petri dish with Teflon tubes) uses fluid transport to perform the basic steps of processing a biopsy sample. This device is expected to automate and streamline the manual process that a pathologist follows to help diagnose a biopsy sample. Another advantage is that this technology would allow for 3-dimensional imaging, unlike the current technique followed by pathologists which only allows 2-dimensional imaging, providing a much more detailed and complete view of the tumor.

VOC Diagnostics, a start-up company that is the brainchild of business school students at the University of Louisville, Kentucky, is developing a lung cancer diagnostic test that has the easiest sample collection technique: the patient simply breathes into a bag. The air from the sealed bag is then released over a diagnostic microchip called VitaLung, also developed at the University of Louisville, which then detects volatile organic compounds in a person’s breath. The results from the patient sample are then compared against the molecular profile (biomarkers) of lung cancer to make a diagnosis. VOC Diagnostics initiated efficacy trials at the beginning of 2013, and early results showed 90% accuracy.

The American Lung Association recommends an annual low-dose computed tomography (LDCT) screen in individuals with a high risk for the disease, such as current or former smokers.

Although beneficial in high-risk individuals, an exhaustive review published in the 

Journal of the American Medical Association

 evaluating the effect of LDCT on lung cancer mortality screening concluded that the screen could potentially be harmful, as it cannot distinguish between benign and cancerous tumors. Therefore, additional imaging to confirm potentially benign nodules increases the patient’s exposure to radiation, while surgeries undertaken to excise benign nodules can result in complications.

Considering these complications, VitaLung is safer and was definitely found to be accurate based on preliminary results.

	1. Trafton A. A paper diagnostic for cancer. Massachusetts Institute of Technology website. http://web.mit.edu/newsoffice/2014/a-paper-diagnostic-for-cancer-0224.html. Published February 24,

	2. Warren AD, Kwong GA, Wood DK, Lin KY, Bhatia SN. Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics. 

	3. Martinez AW, Phillips ST, Whitesides GM, Carrilho E. Diagnostics for the developing world: microfluidic paper-based analytical devices. 

	4. Diagnostics For All website. http://www.dfa.org/projects/projects-overview.php. Accessed March 31, 2014.

May 2014

Everolimus in Elderly Hormone-Receptor-Positive Advanced Breast Cancer Patients

Stem Cells Create a Therapeutic Niche

CVS Caremark Quits for Good: Our Decision to Stop Selling Tobacco Products

The Double Whammy of the Obesity Epidemic: Increased Susceptibility to Cancer

Cheap and Easy-To-Use Diagnostic Tests to Detect Disease Biomarkers, Including Cancer

The Big Data Revolution: From Drug Development to Better Health Outcomes?

Roche Molecular Diagnostic's cobas HPV Test Approved by the FDA

NCCN Panel Asks What ACA Means to Cancer Care Delivery

Fast Track for Prima Biomed's CVac Clinical Trial Development Program

Understanding Which Therapy Comes First in Treating Castration-Resistant Prostate Cancer

Choosing a BRCA Genetic Testing Laboratory: A Patient-Centric and Ethical Call to Action for Clinicians and Payers

New NCCN Prostate Cancer Screening Guidelines Aim for Middle Ground

Denlinger Discusses Posttreatment Surveillance for Cancer Survivors

More Enthusiasm for Newer Melanoma Therapies

When Science Outpaces Payers: Reimbursement in Molecular Diagnostics

Mutations That Drive Lung Cancer Also Driving Frontiers of Treatment

Promising News in Treating Multiple Myeloma

Sorting Through Screening Protocols for Colorectal Cancer

Protecting Bone Health During Cancer Care

The Role of Bioinformatics in Oncology Drug Development-and Precision Medicine