Stanton R. Mehr

The etiology of Crohn’s disease remains a mystery of modern medicine. Since Burrill Crohn, MD, and his associates first characterized this disease of “regional enteritis”

it has been recognized as an inflammatory process that primarily affects the small intestine. The “skip pattern” of inflammation seen on radiologic barium exams perplexed clinicians, but it has served as a key diagnostic sign: one section of the bowel appears highly affected while the adjacent sections appear healthy.

Speculation on what causes Crohn’s disease has evolved over time. Once thought to be the result of simple inflammation, in which the body overreacts to its own stimuli, as in autoimmune disease, theories progressed toward a specific type of inflammatory response. Today’s research is concerned with what might be causing the inflammation. This historical track has been paralleled by the evolution of therapies. When Crohn was a practicing gastroenterologist, the only option was surgery. Then, as inflammation was better understood, agents were developed to shut down the body’s response to inflammation generally (eg, prednisone), to immunosuppression (eg, azathioprine, cyclosporine), to addressing individual factors in the inflammatory process (eg, TNF-alpha inhibitors).

Although effective therapies for treating Crohn’s have been introduced for 50 years, the actual cause of bowel inflammation remains unknown. A combination of factors may be responsible, including food, the environment, and genetics, but scientists have made little progress on key questions. Why does the disease suddenly emerge in adolescence? What causes flare-ups after medical treatment successfully induces a symptomatic remission? And, why do the skip patterns exist, in which only parts of the bowel seem to be susceptible to the disease?

With these questions in mind, researchers are revisiting an older concept: what if a microbe, or microbes, are causing the inflammation? According to unpublished reports, Crohn himself voiced suspicions that a microbe, specifically 

, may play a critical role in this disease. Considering treatment costs and the side effects associated with Crohn’s disease as well as the biologic agents used for treatment, the thought of a simple antibiotic cure would be welcomed by patients, providers, and payers.

Crohn could not directly evaluate the presence of 

 in his day, as the technology needed to detect the organism did not exist. Although a gold standard to culture the microorganism does not exist,

more recent studies have been successful in detecting it in humans.

However, use of these detection methods has not settled the question, and several groups of investigators have obtained mixed results. In 2004, researchers found that 50% of patients with Crohn’s disease and 22% of those with ulcerative colitis tested positive for 

 in the blood, whereas none of the controls (who did

not have inflammatory bowel disease) tested positive.

Others showed that higher levels of this pathogen were not detected in patients with recent—onset Crohn’s disease compared with controls. However, it was found to be present in greater amounts in patients with established disease.

To complicate matters, other investigators failed to establish a link. A 2013 study of intestinal granuloma and lymphatic samples from patients with active Crohn’s disease

and healthy controls, revealed no evidence of 

Also, the use of anti-infective therapy targeted to this organism, in patients with active Crohn’s disease, has not produced beneficial clinical results.

It remains unclear whether the presence of 

 is the result of an incidental association or indicates a causative agent.

 However, the evidence does seem to be mounting that this pathogen is not the “smoking gun” that Crohn and others have sought for the better part of a century.

, then what? Some have focused on other singular 

species, as they all reside close to the intestinal mucosa.

 In fact, it now seems unlikely that a single pathogen will be implicated as the cause.

Perhaps the situation is far more complicated. A theory that has received support is that the overall gut microbiome may play a pivotal role in patients with Crohn’s disease. A 2012 review by Mann and Saeed

had been prevalent in previous studies of patients with Crohn’s disease. The authors conclude, “The majority of recent studies support a role for the ability of intestinal pathogens to promote chronic inflammation in individuals with genetic susceptibility and/or other environmental factors which remain to be identified. These factors may include subsets of commensal microflora.”

 If this is the case, antibiotics in use today may destroy many of the necessary microbes found in the gut or increase the population of pathologic bugs.

The question may not be whether a single pathogen is at work in causing inflammation, but rather, whether the body’s reaction to normal gut bacteria has gone awry. Each person has a combination of microbes in the intestinal tract; some may be responsible for bowel inflammation, while others protect against it. To investigate this, researchers from 28 centers throughout the United States and Canada attempted to characterize the entire microbiome of 447 patients with Crohn’s disease. They compared their results with the microbiome of 221 controls. The samples were collected from throughout the small and large bowel of the patient.

In patients with Crohn’s disease, very few of the beneficial microorganisms were found residing in the gut, while too many pathologic microbes were discovered. Higher numbers of 

 were often found in patients with Crohn’s disease. Dirk Gevers, PhD, the lead investigator, told 

that the real issue may not be the existence of pathologic organisms in the gut. The real problem may be the relationship between the normal organisms and the bowel environment.

Gevers, the group leader of Microbial Systems and Communities in the Broad Institute’s Genome Sequencing and Analysis Program, said, “The organisms are present in both healthy subjects and patients with Crohn’s disease, but only in patients these organisms are present in an imbalanced state, also called dysbiosis.” He added, “This dysbiosis is linked to the disease, but no causative relation has been demonstrated so far. What we were able to show in our work is that a more severe disease state has a more extreme dysbiosis. This might suggest that reversing this dysbiosis could be a potential route for treatment, a route that is actively being explored by several

The theory of dysbiosis received support from a study of patients who relapsed after receiving infliximab therapy. Researchers found that a look back through the patients’ microbiomes revealed markers that predicted relapse. Low concentrations of certain 

Are We Looking in the Wrong Place for a Cure?

If the theory of dysbiosis is true, then treatment options might be in 1 of 2 areas: (1) rebalancing the microbiome through methods such as fecal implantation (such as that used to successfully treat 

or perhaps by using targeted antibiotics to reduce, but not eliminate, the levels of certain organisms along with probiotics to increase the levels of others or (2) an approach that is aimed at restoring the normal relationship between the organisms and the intestinal lining.

“Instead of wiping out a whole gut microbiome with broad spectrum antibiotics,” said Gevers, “new directions that can be explored are those that target the host—microbe interaction with a more subtle approach, either correcting the imbalance or modulating the dysfunctional response of the host to organisms that are otherwise well tolerated by healthy people.”

Uncertainty remains whether the dysbiosis seen in patients in Crohn’s disease is an association or a cause. However, research is proceeding rapidly down this path, and there is much enthusiasm an answer to this riddle of Burrill Crohn’s disease may be on the horizon. 

Articles

The Intestinal Bug Hypothesis in Crohn's Disease Gets a Reboot

Studies conducted more than 15 years ago determined that the annual cost of Crohn’s disease in the United States exceeded $1 billion, with the largest proportion being direct medical costs.

 At that time (1999 to 2000), the use of biologic therapy to treat Crohn’s disease had not yet skyrocketed, and these figures are undoubtedly higher

By 2012, the economic burden of Crohn’s disease was found to be far greater. A retrospective study in Italy found that average direct annual costs associated with a cohort of patients with active disease were €11,838 per patient (approximately $16,000).

 Adding in productivity and other indirect costs raised this figure to €15,521 per year ($21,000), with direct costs representing 76% of the total. According to the Crohn’s and Colitis Foundation of America, 700,000 Americans may be affected by the disease,4 and the estimated direct cost for these patients is $1.84 billion.

Hospitalizations account for most direct costs associated with Crohn’s disease. These are sometimes necessary to treat intestinal obstructions, particularly in patients with long-standing disease. Bowel resection to remove the obstruction can be associated with hospital stays of up to 1 week, with no guarantee that treatment will prevent future obstructions elsewhere in the intestine.

Much literature has been published regarding the expectation that biologic therapies would reduce hospitalizations as well as other medical costs, and that these medications would reduce the cost burden of illness, but so far, the results have been inconsistent. Although these new medications have been shown to reduce hospitalization and other medical resources, the data conflict on whether they are truly cost-effective from a societal viewpoint (when using a cost-effectiveness threshold of $100,000 per quality-adjusted life-year).

The Economic Costs of Crohn's Disease

Multiple studies in recent years have discussed what happens when patients with chronic conditions do not take medications as prescribed. The impact of poor adherence on both health and healthcare costs is so well documented that CMS now asks accountable care organizations (ACOs) to take steps to ensure better adherence when patients leave the hospital, to help hold down readmission rates.

Yet despite the attention to the problem of adherence, alongside data that show increases in life expectancy are hitting plateaus among older Americans,

 it appears less attention has been paid to knitting together evidence on a related question. In this era of healthcare reform, is anyone asking whether challenges with adherence are contributing not only to poor health, but also to lower life expectancy?

The question arises in the wake of a new study led by Johns Hopkins researcher Eva DuGoff, PhD, who in August published results that examined how having multiple chronic conditions at once affected life expectancy. DuGoff’s analysis, based on records from 1.4 million Medicare enrollees and evaluating 21 conditions, found that on average, each chronic condition takes 1.8 years off a person’s life after the age of 67 years.

As DuGoff described in a statement released by Johns Hopkins, that average is based on its cumulative effect on older persons; the first disease takes off only a fraction from the life span, with the effect growing with each additional disease. The results showed that different diseases have different effects on the life span, too. But in her conclusions, DuGoff said the key finding—that there are limits to what can be done for patients who suffer from multiple conditions&mdash;was important for Medicare and Social Security administrators, who have a keen interest in knowing how long beneficiaries will live.

“Living with multiple chronic diseases such as diabetes, kidney disease, and heart failure is now the norm and not the exception in the United States,” DuGoff said. “The medical advances that have allowed sick people to live longer may not be able to keep up with the growing burden of chronic disease.”

While DuBoff joined those calling for increased efforts to prevent chronic disease, left unanswered in her study is how patient adherence to multiple medications—needed to manage all those chronic conditions&mdash;factored into the life expectancy equation. Elsewhere, it has been demonstrated that taking medication consistently is linked to better health.

A review by Boswell and colleagues in The American Journal of Pharmacy Benefits found that the connection between adherence and positive clinical outcome varies depending on the chronic condition, but overall the pattern is consistent: there was a positive relationship between taking medication and good outcomes in 81% of the 79 outcomes evaluated.

Simply put, while it may seem obvious, there’s evidence that if you take your medication, it’s better for your health. Boswell’s review found taking medication was most important for patients who had suffered heart attacks and for those with hypertension, diabetes, high cholesterol, and schizophrenia.

 Perhaps it’s not a surprise that 8 of the 33 early measures of whether ACOs are delivering quality care—which Medicare will examine to determine reimbursement under its Shared Savings Program&mdash;are tied to diabetes and cardiovascular conditions.

While adherence has received plenty of attention in the literature, much of the focus has been on the economic impact—in other words, the question asked is, “How does the failure of patients to take medication contribute to rising healthcare costs?” For example, Health Affairs cited a $290 billion price tag for nonadherence.

 A study from Excellus BlueCross and BlueShield found that in upstate New York alone, the cost of nonadherence was $2.87 billion just for depression, diabetes, hypercholesterolemia, and hypertension.

Mona Chitre, PharmD, vice president and chief pharmacy officer at Excellus Blue Cross and Blue Shield, said, “The number of people who don’t take their medications as directed is nothing short of astounding. This signifies a huge health improvement and cost savings opportunity for our upstate New York regions ($2.87 billion in this 1 part of New York alone). But as you know, the problem of nonadherence is a national issue, and not unique to upstate New York.”

A 5% or 10% increase in adherence can yield hundreds of millions in savings for patients suffering from multiple conditions. For the majority of studies reviewed by Boswell and colleagues, the connection between adherence and death was not specifically measured or reported.

The connection between infarction or the need for revascularization may imply risk of death, but the direct relationship between nonadherence and risk of death has not been well explored.

A study published in the Journal of the American Medical Association did support such a link. In 2007, researchers studied the outcomes of more than 31,000 older Canadian patients who had experienced a heart attack and who subsequently filled a prescription for a statin, beta-blocker, and/or a calcium channel blocker, which was considered a control medication for this study.

The authors, who categorized the patients by their level of adherence, found that “Among statin users, compared with their high-adherence counterparts, the risk of mortality was greatest for low adherers” (adjusted hazard ratio [HR], 1.25; P =.001). The risk of mortality was also elevated among those with intermediate levels of adherence versus the low adherence group (adjusted HR, 1.12; 95% CI, 1.01-1.25; P =.03). The authors found a similar relationship for patients who took beta-blockers. No such correlation was found with mortality in those taking calcium blockers.

In 2014, Canadian researchers published a meta-analysis of studies involving populations taking statin medications. They found that nonadherence with statin medications resulted in up to a 2.54-fold increased mortality.

Research from the National Center for Health Statistics and CDC estimated that approximately 117 million American adults have at least 1 of 10 common chronic illnesses.

 This estimate, based on self-reports from the 2012 National Health Interview Survey, does not consider chronic disease in children, in addition to several other important chronic disorders, including mental health diseases, autoimmune diseases such as inflammatory bowel disease, and multiple sclerosis. This same review estimated that 1 in 4 adults have more than 1 chronic disease,

 and that the likelihood  of having multiple chronic diseases increases with age (

By the age of 65 years, it is more likely that Americans will have 3 or more chronic diseases than 1 or 2.

 The magnitude of this phenomenon in the United States was identified by the Johns Hopkins study, which found that nearly 80% of Medicare beneficiaries (aged 67 years or more) have at least 2 chronic conditions, more than 60% have 3 or more chronic conditions, and more than 33% have at least 5 chronic illnesses.

 A rise in multiple chronic disease overall, coupled with its increased prevalence among older Americans, appears to already be making an impact on the flattening of life expectancy in the United States relative to other developed countries, based on what the Johns Hopkins researchers found.

Reasons Behind Multiple Conditions, Poor Adherence

If adherence is a recognized problem, is  the problem worse when a patient has multiple chronic conditions? Does being older further complicate things? And if so, how?

Preventing nonadherence in the elderly is a difficult challenge, according to Thuy-Tien Dam, MD, assistant professor of medicine at Columbia University Medical Center, New York. “Barriers to nonadherence in the elderly include cognitive impairment, which can impact ‘executive function’ such as paying bills and deciding which mail should be kept and which should be thrown away,” she said, “Adhering to medications also becomes an issue with early or mild cognitive decline, which is very common with aging. Most people over age 65 years who are living in the community are taking at least 3 medications, and these regimens can be confusing for older individuals.”

Nonadherence can also be related to other critical factors, Dam said. “For example, physicians may not have the time to explain to patients why they need to take the medication and how it will help them. Second is the possibility that side effects or drug interactions are causing patients to discontinue the regimen,” she said.

Questions about the ability to pay for medications often arise in studies on adherence. But prescription co-payments are not always be the only issue, or the main issue. In an important 2011 multicenter study of patients who had suffered a heart attack, adherence with pharmacologic therapy ranged between 36% and 49%.

They also found that even if the patients had full coverage for their medications in this study (without any co-payments), adherence rates rose only a maximum of 6 percentage points. However, even with this small increase, the rate of vascular events was still significantly less than in the group with lower adherence (who had usual coverage).

Consider this effect in the older patient with multiple drug regimens for several comorbidities. Said Dam, “I think that nonadherence for several diseases is synergistic, although there’s not much evidence to support this specifically. If you have high cholesterol and hypertension, and you’re nonadherent with 3 of your medications (for any reason), then the risk of having negative cardiovascular outcomes is greater.

“With polypharmacy, the instructions to the patient may be more complex, and it is to be expected that patients will have more difficulty in adhering to their medications. They will also experience more side effects, which can influence patients to stop taking their medication, also resulting in negative health outcomes,” she said. Examples of complex instructions include “Don’t take this medication without a meal,” or “Don’t take these 2 together.”

 reported similar findings when it asked patients with diabetes or asthma to self-report barriers to adherence. Other barriers included failure to get timely refills and simply that there are too many pills to accurately track.

Polypharmacy is one of the greatest challenges in caring for the elderly, according to Renae Smith-Ray, PhD, research scientist at the Center for Research on Health and Aging, University of Illinois at Chicago. She told Evidence-Based Diabetes Management, “One of the main causes of falls among older adults is polypharmacy, and this results in a great deal of disability. It is very unusual to meet an older adult who doesn’t take any medications. Most are taking 3 or more.”

This issue of “nonadherence” affects health promotion as well. In her research on behavioral change, Smith-Ray found that “Adherence to behavior change programs is notoriously difficult. Some reasons may be intuitive—we’re creatures of habit, and making abrupt change is difficult. Although most people know that physical activity is necessary for maintaining good health, physical activity takes considerable exertion relative to other health behaviors. “We know that the initial phase of behavior change is most challenging; that is, when one first begins the new behavior.

Consider an adult with arthritic knee pain: the most tempting thing to do is to keep your feet up on a sofa and remain immobile to prevent pain. It is much easier not to begin an exercise program, and there may be a mistaken perception that exercising will cause more arthritis-related pain. However, we have found exactly the opposite to be true, that improving endurance and lower-extremity strength removes pressure from weight-bearing arthritic joints, which decreases pain.”

Smith-Ray believes that cognitive training programs can also be a useful tool for improving many aspects of health. “Through our research, we found that many participants report a noticeable difference in attentiveness to daily tasks following a 10-week intervention for cognitive training done in a classroom setting.” Perhaps one of these tasks can be taking medication and following other medical recommendations.

“Nonadherence Affects Length of Life”

“Medication adherence is strongly related to both disease progression and control,” stated Vittorio Maio, PharmD, MS, MSPH, associate professor, Thomas Jefferson University School of Population Health. “As former surgeon general C. Everett Koop said, ‘Drugs don’t work in patients who don’t take them.’ There is no doubt, therefore, that poor adherence is consistently associated with poor clinical, economic, and utilization outcomes. Nonadherence affects length of life.”

Maio affirmed, “Clearly, adherence to treatments would become even more important in patients with multiple conditions, a quite common situation in the elderly, because these patients are already at much greater risk of poor outcomes. In these subjects, poor adherence to prescribed treatments would lead to suboptimal clinical responses to medications, which could in turn largely increase the onset of medical (and often lethal) complications as a consequence of poor therapeutic control.”

1. ACO shared savings program quality measures. CMS website. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/sharedsavingsprogram/Downloads/ACO-Shared-Savings-Program-Quality-Measures.pdf. Accessed August 22, 2014.

2. DuGoff EH, Canudas-Romo V, Buttorff C, Leff B, Anderson GF. Multiple chronic conditions and life expectancy: a life table analysis. Med Care. 2014;52(8):668-694.

3. Life expectancy gains threatened as more older Americans suffer from multiple chronic conditions [press release]. http://www.jhsph.edu/news/news-releases/2014/life-expectancy-gains-threatened-as-more-older-americans-suffer-from-multiple-medical-conditions.html. Baltimore, MD: Bloomberg School of Public Health; July 23, 2014.

4. Boswell KA, Cook CL, Burch SP, Eaddy MT, Cantrell CR. Associating medication adherence with improved outcomes: a systematic literature review. Am J Pharm Benefits. 2012;4(4):e97-e108.

5. McKethan A, Benner J, Brookhart A. Seizing the opportunity to improve medication adherence. Health Affairs blog. www.healthaffairs.org/blog/2012/08/28/seizing-the-opportunity-to-improve-medication-adherence/. Published August 28, 2012. Accessed August 2, 2014.

6. Medication adherence among upstate New York adults: a multi-billion dollar health improvement opportunity. Excellus BlueCross BlueShield website. (https://www.excellusbcbs.com/wps/wcm/connect/e3a05c81-35d2-466f-a71a-f8bba660f978/Rx+Adherence+FS-EX+FINAL.pdf?MOD=AJPERES&CACHEID=e3a05c81-35d2-466f-a71a-f8bba660f978). Published August 12, 2014. Accessed August 18, 2014.

7. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality rate after acute myocardial infarction. JAMA. 2007;297:177-186.

8. Choudhry NK, Avorn J, Glynn Rj, et al. Full coverage for preventing medications after myocardial infarction. N Engl J Med. 2011;365:2088-2097.

9. Ward BW, Scholler JS, Goodman RA. Multiple chronic conditions among US adults: a 2012 update. Prev Chron Dis. 2014;11:130389.

10. Rolnick SJ, Asche S, Pawloski PA, Bruzek RJ, Hedblom B. Barriers to and facilitators of medication adherence. Am J Pharm Benefits. 2013;5(5):209-215.

Exploring the Intersection of Chronic Disease, Adherence, and Life Expectancy

Tamoxifen was approved by the FDA in 1977 to treat advanced breast cancer. In 1998, the Early Breast Cancer Trialists’ Cooperative Group published results showing that tamoxifen was effective in preventing breast cancer recurrence in patients whose tumors were estrogen receptor (ER)-positive or of unknown ER status,

 which led to an expansion of the drug’s indication.

 As effective as tamoxifen and other therapies have been, some breast tumors do recur. Despite the considerable scientific data and many successes in treating breast cancer, not much is known about recurrent breast tumors, other than that they can appear in almost any location in the body and at any time after remission is attained—even decades later.

The incidence of breast cancer has remained relatively stable since 2004.

 Declining incidence during the 1990s was attributed in part to lower utilization for estrogen replacement therapy for the treatment of menopausal symptoms.

Alongside a stable level of breast cancer incidence, breast cancer deaths have dropped 34% since 1990.

 Better therapies have led to improved 5-year survival rates, which vary by race (90% for Caucasians and 79% for African Americans) and by stage at the time of diagnosis (

). The relative survival rates at 10 and 15 years are 83% and 78%, respectively, for diagnosis at any stage.

 As a result, the number of breast cancer survivors is accumulating; about 3.1 million Americans are breast cancer survivors, defined as those patients who have completed active treatment.

Despite these encouraging statistics, mortality is still high among patients who are initially diagnosed with advanced-stage breast cancer. For patients who are initially diagnosed with earlystage disease, recurrent breast cancer remains a principal cause of death,

 which may occur years afterward: the old philosophy that patients who do not demonstrate tumor recurrence for 5 years are “cured” has been replaced by the more precise observation that they remain “cancer-free.”

. Breast cancer survivors may live cancer-free for the remainder of their lives, but several other outcomes are possible. These include (1) living cancer-free for many years but having a late recurrence, (2) living cancer-free for many years but developing a second cancer, (3) having intermittent periods of treatment for active disease, or (4) living with cancer without any disease-free periods of time.

Up to one-fifth of breast cancer survivors will experience a recurrence.

 The rate of recurrence at 10 years has declined since the 1980s and 1990s, when it ranged from 8% to 19%, to 2% to 7% in the past decade, depending on multiple factors. Whether a breast cancer survivor experiences a recurrence can depend on age at initial diagnosis, genetic background, what stage the cancer is at diagnosis, receptor type, histologic and nuclear grade of tumor, and how the original tumor was treated.

Recurrence, which may not necessarily be the same tumor reappearing, can be 1 of 3 types

• Local recurrence. Cancer recurrence is in the same localized area of the breast (ipsilateral) as the first tumor, or in the mastectomy scar. When breast cancer appears

in a different quadrant of the breast from the original tumor or in the other breast (contralateral), it is usually a new tumor.

• Regional recurrence. The cancer is in nearby lymph nodes (eg, under the arm or around the collarbone).

• Distant recurrence. The cancer appears in another part of the body that is some distance from the original site (eg, bone marrow, lungs, liver, brain).

Part of the challenge is determining whether a second appearance of cancer is a recurrence or a new cancer. Regional and distant recurrence likely represent completely new tumors. For example, a recurrence that appears in the liver 10 years after the initial breast tumor is treated with agents appropriate to the tumor location (ie, using  hepatic cancer therapies vs breast cancer therapies).

A small study in the mid-1990s found that 36% (N = 18) of the primary tumors that were ER-negative and progesterone receptor (PR)-positive were instead ER-negative and PR-negative in their recurrent form, while tumors that were initially receptor-negative remained so on recurrence. The authors concluded that the loss of ER expression in recurrent breast cancer may be the reason recurrent tumors respond poorly to endocrine therapy.

This finding suggested a distinct profile of the recurrent tumor. Patricia Ganz, MD, director, Cancer Prevention and Control Research, and director, Patients and Survivors Program Area, of the UCLA Jonsson Comprehensive Cancer Center, told 

, “Breast cancers are made up of a mixture of cells. As a result, the recurrence may not be exactly like the primary tumor and may represent a subset of cells that disseminated. So we sometimes see tumors that were HER2 (human epidermal growth factor receptor)-negative initially show evidence of HER2 at recurrence. Likewise, tumors that were ER-positive

or -negative may change. The majority of recurrences—about 85%&mdash;are same as primary.”

Two-thirds of breast recurrences are identified as being a local recurrence, with the tumor recurring in the same breast in the same place or close to the original tumor; these cases are considered new growth of the old tumor. When there is a local recurrence, it usually occurs within 5 years of the initial breast cancer diagnosis.

After initial treatment, approximately 15% of breast cancer survivors will develop a second breast malignancy within 10 years,

 and about 40% of patients who experience recurrence have a regional recurrence in both the breast tissue or the chest wall, and in the lymph nodes. Fewer than 5% of patients have a recurrence that appears just in the lymph nodes, usually the:

• internal mammary (under the chest wall along the breastbone)

• infraclavicular (just below the collarbone)

• axillary (underarm area) closest to the original tumor site

• axillary on the contralateral side (this is rarely seen)

. Most women diagnosed with breast cancer are older than 65 years (median age, 61 years). However, one-fifth of those diagnosed are younger than 50 years.

 Past studies have shown that patients diagnosed at a younger age have a greater chance of recurrence than those diagnosed at an older age. Even with advances in therapy, younger women are more likely to experience a local recurrence (

Breast Cancer—Receptor Type and Recurrence

. Estrogen plays a major role in the development and progression of breast cancer. Seventy-five percent of breast cancer tumors express ER, and 55% express PR. HER2 also plays an important role in the development and progression of breast cancer. There are 5 molecular breast cancer subtypes, 4 of which are most commonly observed—luminal A, luminal B, HER2 type, and triple negative.

 Many times, luminal A and luminal B are combined into 1 subtype, estrogen/progesterone-positive.

Patients with hormone receptor—positive tumors have a recurrence rate that is twice as high as those with hormone receptor–negative tumors at 5 years posttreatment.8 Women with ER-positive tumors have a greater risk of recurrence in later years than in the first 2 years.

 Overall, ER-positive tumors are associated

with a long-term recurrence rate of 2% per year but are less likely to cause death from breast cancer than other tumor subtypes.

 Overall, patients with hormone receptor-positive tumors have the best outcomes.

ER-negative tumors mostly recur during the first 5 years, whereas the ER-positive tumors recur later.

 By 15 years after diagnosis, the risk for recurrence is the same for both receptor types.

Triple-negative breast cancers (TNBC) have a high risk of recurrence, especially for distant recurrences, compared with receptor-positive tumors.

 However, patients with TNBC who do not experience a recurrence within 5 years are more likely to remain cancer-free than patients with ER-positive tumors.

 A study by Miller and colleagues revealed that 15% of locoregional HER2-positive tumors recurred after 5 years, compared with 1% of luminal A tumors.

Influence of Treatment Type on Recurrence

. Evaluating a patient’s risk of breast cancer recurrence is further complicated by another factor: treatment of the initial cancer.

 The risk of distal recurrence is the same for patients having had a mastectomy or a lumpectomy plus radiation therapy.

Patients undergoing lumpectomy plus radiation therapy have an absolute risk reduction of 16% for any recurrence (locoregional or distant) within 10 years.

For patients who had a mastectomy, local recurrence will usually be observed 3 to 5 years after the surgery.

When breast-conserving therapy approaches are used to treat early breast cancers, an annual incidence rate of local recurrence of 1.3% to 1.7% has been observed between 2 and 7 years following the initial treatment. The annual recurrence rate drops to 0.4% per year beginning at 10 years after initial treatment.

 Recurrence rates are similar for women with ER-positive and ER-negative original tumors when treated with breast conserving surgery or mastectomy.

Including radiation therapy for patients with ER-positive tumors lowers their probability of an ipsilateral recurrence, compared with those who have ER-negative tumors. In cases of recurrence, patients with ER-positive tumors present better outcomes than those with ER-negative tumors.

For patients with hormone receptor—positive tumors who are treated with endocrine therapy for 5 years after their initial therapy, 20% will have a recurrence by 10 years of completing their treatment, with twice as many having a recurrence during the first 5 years than in the second 5 years.8,21 In a study by Cadoo and associates,

in half of the tumors that recurred in patients treated with tamoxifen, recurrence was observed between 6 and 15 years from diagnosis. A study by Davies and associates

showed that continuing tamoxifen for 10 years, rather than 5 years, further reduced the risk for recurrence, especially after 10 years. Adjuvant endocrine therapy for hormone receptor—positive tumors reduces the risk of recurrence by up to half.

The American Society of Clinical Oncology (ASCO) recently updated its guidelines to recommend 10 years of adjuvant endocrine therapy, rather than the 5 years previously recommended, to lower the risk of breast cancer recurrence and contralateral

More long-term studies will help guide the treatment of patients with hormone receptor—positive tumors to prevent recurrent breast cancer.

Patients with HER2-positive tumors have a greater chance of local recurrence than patients with ER-positive and HER2- negative tumors after both breast conserving surgery and mastectomy. These patients have a greater chance of a local recurrence than patients with triple-negative tumors; however, after a mastectomy, patients with TNBC seem to have a greater chance of local recurrence.

Interestingly, patients with TNBC who have breast-conserving therapy with radiation have a lower risk of a local recurrence than those who have a mastectomy without radiation. These patients also have an increased risk for distal recurrence that peaks around 3 years, and

after 8 years, distal recurrences are typically not observed.

Even after adjuvant chemotherapy, the risk for recurrence is the greatest in patients with HER2-positive and TNBC tumor subtypes.

Ganz added that this aspect has not been well studied. “Registries do not track this information accurately,” she said. “There is something called the Metastatic Breast Cancer Alliance, which is a consortium of advocacy groups trying to advocate for more information on this.”

gene mutations increase a woman’s risk for developing breast cancer. Individuals with these mutations are also at a higher risk for contralateral breast cancer after having been diagnosed and treated for an initial breast tumor compared with those who do not have such mutations (26% vs 3%).

Other factors that appear to influence the risk of recurrence are levels of Ki-67, a cellular marker for cell proliferation, CK 5/6, p53 markers of basal-like tumors, and bcl-2, a proto-oncogene located on chromosome 18. Multiple genes that are potential markers for recurrence are included in the Oncotype DX (21 genes), Mammostrat (5 genes), MammaPrint (70 genes), and PAM50 (50 genes) genomic assays.24,25

. Many of the risks for the recurrence of breast cancer cannot be altered. However, lifestyle modifications and monitoring for the recurrence of breast cancer may be strategies that can reduce the risk of recurrence. In fact, key resource recommendations have been developed for appropriate survivorship care

Trying to Better Understand Breast Cancer Recurrence

Advances in treatment and in understanding the genomics of breast cancer have led to improved 5-year survival in those patients diagnosed with and treated for breast cancer. However, we do not as yet have a thorough understanding of the patients who have a recurrence of their cancer or who develop another tumor.

According to information from provided by the American Cancer Society to 

, there are no registries that accurately track characteristics of patients and their tumors, and who experiences a recurrence. A better understanding of whether patients at longterm risk for recurrence may redevelop their cancer or develop a new tumor may assist in reducing this risk further, and in optimizing the treatment options available to them.

In the meantime, the concept of a “cure” in patients with breast cancer is more ambiguous than ever: patients in breast cancer survivorship programs with long-term remissions are increasingly being considered to have chronic disease, rather than acute episodic cancers. Ganz commented, “This is pretty common now for patients with HER2-positive disease or hormone receptor—positive disease.” The problem is that we really don’t know how many people can be addressed in this way. “Exact numbers are not available,” she said, “but we’re hoping to get a handle on this.” 

1. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of randomised trials. 

2. Tamoxifen information. FDA website. http://web.archive.org/web/20070619012859/http://www.fda.gov/cder/news/tamoxifen/. Published March 8, 2001. Accessed September 14, 2014.

3. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. 

4. American Cancer Society. Cancer facts and figures 2014. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/. Atlanta, GA: American Cancer Society; 2014. Accessed September 12, 2014.

5. About breast cancer: breast cancer statistics. Susan G. Komen Foundation website. http://ww5.komen.org/BreastCancer/AboutBreastCancer.html. Published March 15, 2014. Accessed June 24, 2014.

6. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2014-2015. www.cancer.org/acs/groups/content/@research/documents/document/acspc-042801.pdf. Accessed June 23, 2014.

7. Ahmad A. Pathways to breast cancer recurrence. 

. 2013; Article ID 290568. doi:10.1155/2013/290568.

8. Dinh T. Statistics on breast cancer recurrence. Livestrong.com. www.livestrong.com/article/55159- statistics-breast-cancer-recurrence/. Published March 12, 2011. Accessed June 23, 2013. 9. American Cancer Society. What are the types of cancer recurrence? www.cancer.org/treatment/survivorshipduringandaftertreatment/ understandingrecurrence/livingwithuncertainty/fear-of-cancer-recurrence-typesof-recurrence. Published June 2013. Accessed June 23, 2014.

10. Local recurrence. Breastcancer.org. www.breastcancer.org/symptoms/types/recur_metast/where_recur/local. Published September 2012. Accessed June 23, 2014.

11. Kuulksdjstbin Y, Konen J, Helin H, et al. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. 

12. Survival and risk of having cancer return after treatment (recurrence, relapse). Susan G. Komen Foundation website. http://ww5.komen.org/ BreastCancer/SurvivalandRiskofHavingCancer-ReturnAfterTreatment.html. Published April 2014. Accessed June 23, 2014.

13. Schneble EJ, Graham LJ, Shupe MP. Future directions for the early detection of recurrent breast cancer. 

14. Regional recurrence. Breastcancer.org.www.breastcancer.org/symptoms/types/recur_metast/where_recur/regional. Published September 2012. Accessed June 23, 2014.

Recurrence of Breast Cancer Years After the Initial Tumor

Rapid innovation in treating type 2 diabetes mellitus (T2DM) has challenged primary care physicians (PCPs) and endocrinologists alike to stay current. Clinicians have a high comfort level with prescribing metformin as a first step after changes in diet and exercise in a patient with newly diagnosed T2DM. However, monotherapy with metformin may work only for a short time for a few patients to sufficiently lower glycated hemoglobin (A1C) levels, owing to the deteriorating nature of beta-cell function.

The typical second step, if hyperglycemia persists, has been to add a sulfonylurea (SU), like glipizide; however, clinicians often wait too long before adding the second medication, thus limiting its effectiveness.

 As a result, consensus is growing to begin combination therapy earlier in treatment. This more aggressive approach to controlling glycemic levels early on, studies suggest, will preserve beta-cell function down the line; the goal is to prevent serious long-term consequences such as kidney disease, neuropathy, and glaucoma.

Although metformin and SU have long been the top choices for initial antidiabetic drug treatment, other noninsulin choices for step 2 therapy abound, from Actos (pioglitazone) to Victoza (liraglutide [rDNA origin] injection). To compound the choice facing clinicians, many manufacturers, when conducting mid-stage and late-stage clinical trials, include a monotherapy trial of their glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 inhibitor (DDP-4), thiazolidinedione, metglitinide, or sodium-glucose cotransporter 2 (SGLT-2) agent. These are often shown to be effective in placebo-controlled clinical trials.

In its 2014 update, the American Diabetes Association (ADA) revised its Clinical Practice Recommendations for treating T2DM. A significant change from past recommendations is a shorter trial of noninsulin monotherapy to control hyperglycemia. According to the new guidelines, physicians should wait no longer than 3 months (instead of up to 6 months) in an average patient before moving to combination therapy.

 If adopted, this practice would compel clinicians to decide earlier which second-line therapy is best for their patients. For many, this means prescribing an SU, which they have been doing for years in patients who do not have contraindications.

For others, the more innovative choices can be both attractive and daunting.In its 2014 standards of medical care, the ADA provides open-ended advice: “If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a glucagon-like peptide 1 (GLP-1) receptor agonist, or insulin.”

 In other words, there is little specific information (and evidence) to help providers choose.

In these studies, insulin-based combinations, rather than metformin/SU, are used as the first drug combination. (Some of these studies were previously reported in 

This change is being driven by an overarching clinical and physiological philosophy, according to John Anderson, MD, of the Frist Clinic in Nashville, Tennessee: Stop beta-cell deterioration by getting patients to goal A1C levels as soon as possible. He said that ideally, one would screen patients with prediabetes and treat them at that point with lifestyle interventions or metformin.

“By the time patients are diagnosed with diabetes, we need to get them to glycemic goal as quickly as possible and keep them there as long as you can to reduce beta-cell damage and the long-term risk for micro- and macrovascular disease,” Anderson said.

However, patients are infrequently diagnosed with prediabetes, and may have significantly elevated A1C levels when they are first seen by the clinician. Anderson explained, “If you can get them to goal on metformin monotherapy, that’s fine, but if the patient is first diagnosed with an A1C of 8.5% or 9%, you have precious little chance to get them to goal with 1 treatment. In that case, we need to make changes to their treatment as soon as is feasible. For that patient, you may need to start out not on monotherapy, but on combination therapy.”

Sparing beta cells or limiting beta-cell deterioration has long been an ultimate objective of T2DM care.

 New studies have demonstrated that using insulin early in the natural history of the disease can actually produce short remissions in hyperglycemia and slow beta-cell dysfunction. Furthermore, investigators found that this occurred after only a few weeks of therapy.

 This offers patients the possibility of using insulin early, but not continuously injecting it for the rest of their lives. In this scenario, GLP-1 treatment (which seems to have positive effects on beta-cell number and function)

 would be used as maintenance therapy over the long term. This concept is based on an innovative way of thinking about the origins of diabetes, involving the interaction of fatty acids and glucose—a “glucolipotoxicity.”

Novo Nordisk has already developed the idea of a full-fledged combination of insulin and GLP-1, called Xultophy. This combination comprises Novo Nordisk’s new insulin formulation (degludec) and the company’s already approved GLP-1 injectable (liraglutide). The company has filed for approval of the drug combination in Europe, where insulin degludec is already approved. One interesting benefit of this therapeutic combination is that liraglutide’s ability to induce weight loss may help offset insulin’s common side effect of weight gain.

At the recent ADA Scientific Sessions, investigators reported the 1-year results of using Xultophy (IDegLira). Researchers reported that 78% of those taking the combination achieved an A1C level of 7% compared with 63% of those taking insulin degludec alone or 57% of those trying liraglutide monotherapy. The main trial included more than 1600 patients, and the study extension to 1 year, more than 1300. In this investigation, patients taking the combination therapy lost a mean 0.9 pounds compared with a mean 5.1-pound gain for those taking insulin degludec only. Additionally, those taking the combination treatment used an insulin dose that was 37% lower than the dose used by those taking insulin degludec alone. The rate of hypoglycemia was also 37% lower with Xultophy than with the basal insulin alone.

Stanton R. Mehr

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