This is the final article in a series of 3 that highlights results from a national survey of patients with cancer.

 The first 2 articles discussed patients’ perceptions about their treatment

 and how medical staff communicated information about their disease and treatment plan.

 This article focuses on the financial concerns of cancer treatment.

The survey involved 418 patients who within the past 5 years had, or still have, cancer. All patients were aware of their health insurance/prescription drug coverage status and most patients (97%) stated that their prescription drugs were covered by health insurance (41% had health insurance through their employer; 31% had health insurance through a state or federal agency).

Impact of Cost or Insurance Coverage on Cancer Treatment

A total of 90% of respondents indicated that they did not have any cost or insurance coverage rules preventing them from taking prescribed medications, receiving treatments ordered for them, or utilizing their preferred physicians and hospital (

). Overall, these results showed improvements from the 2010 survey results.

In most cases, medication was covered by the patient’s health insurance plan; however, 17% of patients indicated that a prescription ordered by the doctor was not filled by their pharmacist due to insurance coverage reasons. This is a lower percentage than that observed in the 2010 survey (25%).4 In most cases, patients were able to find a way to obtain their medication or a similar medication (

). Among patients receiving intravenous chemotherapy, 40% had to pay some form of a drug copay (

Among 98 patients using the Medicare Part D drug plan, 15% stated they had reached the donut hole (compared with 30% of Part D respondents from the 2010 survey who stated they reached the donut hole).4 Of those in the donut hole, 86% continued taking their medications and paid out of pocket (

). The remaining patients stopped taking their medications or switched to generic or lower-cost brand medications and paid for them.

Survey results indicated that most patients took multiple medications, with 54% stating that they took 1 to 3 prescriptions, 24% that they took 4 to 5, and 22% that they took 6 or more. Although most patients took their medication as prescribed,

• 42 (10%) patients stopped taking their medication

• 30 (7%) patients did not fill their original prescription

• 39 (9%) patients did not refill their medication.

The top 3 reasons for nonadherence were side effects, a perceived lack of efficacy, and the cost of medication (

). Among patients who stopped taking or did not refill their medication, one-third to one-half indicated that additional counseling would have corrected their behavior (

In most cases, patients with health insurance were able to obtain their medication. Compared with 2010 survey results, patients encountered fewer obstacles in receiving treatment and using preferred doctors and hospitals. This may be due, in part, to certain provisions of the Patient Protection and Affordable Care Act being implemented in 2011, such as the 50% discount on branded drugs for Medicare Part D enrollees as they enter the donut hole, or the requirement that employers eliminate caps on annual or lifetime coverage.

 please e-mail your request to: eisaioncologydigest@eisai.com.1. 2012 Eisai Oncology Digest. Woodcliff Lake, NJ: ReCon Marketing Solutions, LLC; 2012.

2. Trends in the 2012 Eisai Oncology Digest: patient demographics and cancer treatment goals. Am J Manag Care. 2012;4(3):136-138.

3. Trends in the 2012 Eisai Oncology Digest: counseling and communication of cancer treatment. Am J Manag Care. 2012;4(4):184- 186.

4. Eisai Oncology and Senior Health Digest. Woodcliff Lake, NJ: Cooper Research; 2010.

Articles

Evidence-Based Oncology

Trends in the 2012 Eisai Oncology Digest: Insurance and Cost Obstacles in Cancer Treatment

Even with a greater emphasis on prevention of colon cancer, it is still high on the radar of policy makers, practitioners, and the biopharmaceutical industry. This is related to the impact it continues to have on our society.

The number of deaths caused by colon cancer has trended significantly lower since 1998, with the greatest decline seen in women.

 Even accounting for the decrease in deaths, about 103,000 persons will be diagnosed with colon cancer this year and about 52,000 will die of either colon or rectal cancer in 2012,

 making it the second-leading cause of cancer-related deaths in the United States.

The incidence of disease rises with age, and the decile group most affected by colon cancer remains those between the ages of 65 and 74 years, followed by those 55 to 64 years of age. The median age of patients with colon cancer is 69 years, and the highest frequency of diagnoses is among African Americans, followed by Caucasians.

As is the case with many oncologic disorders, the 5-year survival is greater for those diagnosed at earlier stages of disease (Table). Greater use of screening is believed to be the key reason for declining colon cancer mortality, resulting from earlier diagnosis.

 This may be related to the availability of new screening technologies as well, such as capsule endoscopy or virtual colonoscopy

National guidelines recommend screening beginning at age 50 years and continuing until 75 years, with people at higher risk beginning screening at a younger age.

 The government estimates that as many as 60% of colorectal cancer deaths could be prevented if the screening guidelines were followed.

 Even though death rates associated with colon cancer are falling, there is much room for improvement: screening remains underutilized, with less than 60% of age-eligible patients being fully compliant with screening test guidelines.

 Many patients have not had any appropriate colorectal screening or only underwent a single screening.

As mentioned earlier in this article, patients with an earlier diagnosis have better 5-year survivals. Treatment strategies for colon cancer are guided by the stage of the disease with surgery, chemotherapy, targeted biologic therapy, radiation therapy, and combined therapies most often employed.

Colon cancers are classified by stage 0, I, II, III, or IV and recurrent disease.

 This refers to the depth of the tumor through the intestinal wall and of course the extent of its spread. Surgery for Stage 0 and I disease is considered curative, and adjuvant chemotherapy is not required. Stage II disease is treated with surgery, with about 80% of patients being considered cured with surgery alone.

 The need for adjuvant chemotherapy is usually limited to high-risk stage II disease

; adjuvant chemotherapy in this setting is thought to reduce the risk of death by only 5%.

 Approximately 50% of patients with stage III disease are cured with surgery alone, and adjuvant chemotherapy reduces the risk of death by 15% to 20%.

Therefore, for stage III colon cancer, chemotherapy beyond surgery is prescribed for most patients. Depending on the patient’s health, surgery may not be performed in patients with stage III disease. Surgery may or may not be performed in patients with stage IV disease. Some of these patients may require chemotherapy before surgery (ie, neoadjuvant) can be performed, in an attempt to reduce the size of the tumor and increase the probability of a successful, complete resection.

Common therapies for colon cancer include the traditional chemotherapy agents 5-fluorouracil, capecitabine, irinotecan, leucovorin, and oxaliplatin, with the targeted biologic agents bevacizumab, cetuximab, and panitumumab being utilized for metastatic colon cancer. In July 2012, the US Food and Drug Administration (FDA) expanded the indication for cetuximab for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) for firstline treatment of patients with K-RAS mutation-negative (wild-type), EGFRexpressing metastatic colorectal cancer.

A new therapeutic entity, an angiogenesis inhibitor, ziv-aflibercept, was approved by the FDA in August 2012 for use in combination with FOLFIRI for metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen.

 The median overall survival was 13.5 months in the group receiving ziv-aflibercept plus FOLFIRI compared with 12.1 months in patients receiving FOLFIRI only (hazard ratio [HR], 0.82). The ziv-aflibercept plus FOLFIRI group also had an improved median progression-free survival, 6.9 versus 4.7 months (HR, 0.77). Both measures were found to be statistically significant.

Although only 2 medications have been approved to date in 2012 for colon cancer, more than 100 medications for colorectal cancer are being currently investigated for this indication, with the majority being targeted agents.

 In June 2012, priority review was given to the new drug application for regorafenib, an oral multikinase inhibitor, for patients whose disease has progressed after approved standard therapies. The FDA approved regorafenib on September 27, 2012.

 In a clinical trial, the median overall survival was 6.4 months for the regorafenib group compared with 5.0 months in the standard treatment group (HR, 0.77). Progressionfree survival was also improved in the regorafenib group (HR, 0.49).

Most colon cancer begins as a neoplastic polyp that progresses slowly over 10 to 15 years.

Because of the slow growth, colon cancer can effectively be screened, resulting in patients avoiding a diagnosis of colon cancer or having their cancer diagnosed at an early stage.

The currently available screening tools include colonoscopy, flexible sigmoidoscopy, barium enema, and fecal occult blood testing. Traditional colonoscopy is generally considered the gold standard, as polyps can be directly observed and removed as needed. However, there is some difference of opinion as to the best procedural preparation (which can discourage patients from having repeat colonoscopies at their recommended intervals) and to the need and insurance coverage of anesthesia during the procedure. Another more recent development has been the use of virtual colonoscopy and capsule colonoscopy.

In virtual colonoscopy, a 3-dimensional image is generated using multiple x-rays. To prepare for a virtual colonoscopy exam, the patient must use laxatives or enemas to empty the colon before the procedure. This noninvasive screening tool is considered to be more cost-effective than the standard colonoscopy when polyps are smaller than 6 mm in diameter. Clinical guidelines consider polyps below this size not to be clinically significant. The cost per life-year gained was found to be $4361 for a virtual colonoscopy versus $9180 for a standard colonoscopy.

Another screening tool option being explored is a capsule colonoscopy. With capsule colonoscopy, patients use a standard lavage regimen before swallowing a capsule with imaging equipment aboard. The capsule takes images of the bowel wall as it transits and sends the images generally through radio frequency transmission to a receiving device worn around the patient’s waist, which stores the images for later review.

 A study in Germany showed that capsule colonoscopy helped increase the patient uptake of colon cancer screening, although the sensitivity for detecting cancerous lesions was not considered to be acceptable.

 Another study confirmed these sensitivity results for capsule endoscopy for detecting colon polyps.

Clearly, improved accuracy will need to be proved before capsule endoscopy acceptance for colon cancer screening in the United States. A second-generation product does suggest the potential for improved accuracy, but additional studies are needed to confirm this finding.

In either capsule or virtual colonoscopy, a traditional procedure may also be required to remove any polyps visualized on the images, but it may somewhat reduce the need for difficult preparations and possible costs associated with the endoscopic procedure. Stool DNA testing would also be a non-invasive strategy for screening for colon cancer; however, the US Preventive Services Task Force does not recommend the use of this type of screening, nor does Medicare pay for this screening test. Currently, there is 1 such test available, ColoSure, which is not approved by the FDA. A recent study, however, has found that colorectal cancer can be detected with a high level of accuracy using a stool DNA test.

 A test developed by Exact Science is projected to be available in 2012 or 2013 that will comprise several key markers including stool DNA.

The direct costs for treating colorectal cancer in 2010 were $14.1 billion, with the majority of costs in the initial phase of care followed by the last year of life care and continuing care (42%, 30%, and 28%, respectively).

 It should be noted that these costs do not include screening and prevention costs. Costs for treating the different stages of colon cancer vary greatly, with early stage costing less than late-stage cancer ($30,000 vs $120,000 per patient based on 2007 data).

Hence, the burden of disease for patients and society is much less when colon cancer is found at the earliest possible stage. Indirect costs, specifically the loss of productivity due to colon cancer—related illness and death, were estimated to be $10.7 billion in 2005.

Advances in drug discovery have contributed to the improved overall survival of patients with metastatic colon cancer.

 Economic evaluations of traditional chemotherapy agents have demonstrated that they are costeffective for treating metastatic colon cancer.

 Recently, an evaluation was performed of published cost-effectiveness analyses with the 3 targeted biologic agents, bevacizumab, cetuximab, and panitumumab. For first-line therapy, the authors concluded that these agents can be cost-effective when predictive biomarkers are utilized before initiating therapy; however, additional studies are needed for patients who have proven refractory to other treatments.

Clinical guidelines/pathways have been developed by oncology organizations (ASCO, NCCN, US Oncology) to reduce the variation in practice and improve the quality of care based on the existing evidence supporting each regimen. They found that adherence to Level I Pathways utilized by US Oncology yielded shorter durations of therapy, lower rates of chemotherapy- related hospital admissions, and reduced costs.

Given the variance in cost of treating early and late-stage colon cancer, it would be prudent to place emphasis on the early detection of colon cancer. Studies have demonstrated that all colorectal cancer screening strategies are cost-effective versus no screening.

 It has been determined in cost-effectiveness analyses that the estimated average cost per life-year gained ranged from $5700 to $39,000 for colon cancer screening.

 With the increasing costs of medications utilized to treat colon cancer, screening may actually double the treatment savings, thereby helping to the reduce the costs of managing colon cancer.

EBO: From the payer’s perspective, what are the most effective ways to optimize the value of medications for colon cancer today?

Targeted molecular diagnostics are essential for determining efficacy of immunotherapeutics for treatment of advanced colon cancer. Concomitantly with diagnosis and appropriate aggressive treatment for metastatic colon cancer, patients should be counseled on end-of-life planning and palliative care, since studies show that many patients with advanced metastatic disease mistakenly believe that these therapies are likely to cure them.

EBO: Where do you think we’ve made the greatest strides in colon cancer management over the past decade?

 Widespread improvement in colon cancer screening rates and use of FOBT has been achieved over the past decade. Additional effort in this area should be made to address some recent declines in colon cancer screening rates.

EBO: What do you see as the greatest challenges for better colon cancer detection and management in the coming years?

Modifications to health plan coverage and increasing difficulty in access to primary care services may lead to diminished detection of colon polyps and early stage colon cancers. Alternative means of access to cancer screening and additional programs and methods for colon cancer screening should be employed.

EBO: Do you believe that capsule or virtual colonoscopy systems can improve adherence with colon cancer screening guidelines?

Virtual colonoscopy systems can improve colon cancer screening rates in some limited situations, and as the imaging technology continues to improve, virtual colonoscopy may become the screening tool of choice. Its less-invasive nature may lead to some increases in patient compliance with colon screening programs. Capsule systems offer similar advantages of being less invasive, but technological performance of these systems has not yet achieved parity with conventional techniques, although that will likely change with time.

EBO: Do you think that managed care organizations will more closely scrutinize colorectal cancer management in the future because of the increased use of specialty drugs?

The high cost and limited indications for use of targeted specialty drugs will most definitely lead to close scrutiny and management of colorectal cancer treatment in the immediate future.

Dr Sokolov is chief medical officer at AccelusHealth Partners in South San Francisco, CA.

Strategies to Increase the Value of Colon Cancer Medications

Breast cancer was one of the first disorders to profit from the successful application of targeted therapy, and its treatment has changed dramatically from 20 years ago. Despite these advances, breast cancer is responsible for 14% of cancer deaths among women, second only to lung cancer.

The death rate has decreased since 1990; however, it is projected that about 40,000 will die in 2012 due to the disease (approximately 39,500 women and 400 men),

with the most deaths occurring among African Americans, followed by Caucasians (

 The overall 5-year survival for 2002 to 2008 was 89%, with the longest survival rate in patients having localized disease (98%) and a much lower survival for those with metastasized disease (24%).

An estimated 227,000 new cases will be diagnosed in 2012, and it is the most frequently diagnosed cancer in women. The incidence of breast cancer had declined by the year 2000 and has since remained stabilized.

 The highest incidence is seen in Caucasians, followed by African Americans.

 Breast cancer remains a cancer that is most often diagnosed in older women; about onefourth of the cases will be diagnosed in women between the ages of 55 and 64 years, followed closely by women between the ages of 65 and 74 years.

Factors responsible for the reduction in deaths are reduced utilization of hormone replacement therapy for menopausal women, earlier tumor detection, and improved therapies.

High Incidence Results in Significant Economic Burden

Direct costs in 2010 for breast cancer care were $16.5 billion, which accounted for about 13% of all direct costs attributed to cancer care in the United States.

 In a review of US cost-of-illness studies for breast cancer, the lifetime perpatient costs ranged from $20,000 to $100,000, with higher costs associated with managing patients with advanced disease.

The Susan G. Komen Foundation estimated an average cost of $22,000 to manage the early stages of breast cancer, whereas stages 3 and 4 of the disease are associated with treatment costs in excess of $120,000.

 A Medicare analysis revealed a mean $110,000 direct lifetime cost of patients with metastatic breastcancer.

Average direct costs of breast cancer in a managed care population were calculated to be $2896 per member per month (PMPM), with hospitalization accounting for the greatest share, followed by medications and surgical interventions.

The indirect costs of productivity loss associated with morbidity and premature mortality are much greater: 89% of all breast cancer costs are indrect costs.

 Another study found, using 2007 data, that patients with metastatic breast cancer cost $12.2 billion, or $98,571 per patient per year (including direct medical, palliative/best supportive care, and lost productivity costs).

 Even though there are discrepancies in cost, the societal costs of breast cancer remain high, pointing to the importance of early detection and cost-effective treatment regimens with a goal of curing the disease.

Current Treatment Guided by Genetic Markers

Breast cancers are classified according to hormone receptors and human epidermal growth factor receptor-2 (HER2) status.

Approximately 70% of breast cancer tumors express a hormone receptor (estrogen or progesterone), and about 20% demonstrate HER2 overexpression.

 Recent research has found that there are 4 distinct types of breast cancer, each with its own genetic pattern (

). Of special interest was that triple-negative breast cancer, also known as basal-like breast cancer, was found to have characteristics similar to ovarian cancer, thus offering new therapeutic options to be used to treat this type of cancer.

Knowing the type of breast cancer the patient presents with guides the clinician in treating the tumor.

Treatment options include radiation, lumpectomy, mastectomy, chemotherapy, or a combination of these options.

Chemotherapy for breast cancer includes traditional chemotherapy, hormonal therapy, and targeted therapy. Examples of chemotherapy medications are: anthracyclines (doxorubicin, epirubicin), taxanes (paclitaxel, docetaxel), anti-metabolites (capecitabine, gemcitabine), microtubules inhibitors (vinorelbine, eribulin), and others (5-fluorouracil, cyclophosphamide, mitoxantrone, cisplatin, etoposide, vinblastine, ixabepilone, and methotrexate).

Hormonal therapy includes the agents tamoxifen, toremifene, nonsteroidal aromatase inhibitors (anastrozole and letrozole), steroidal aromatase inactivator (exemestane), fulvestrant, megestrol acetate, fluoxymesterone, and ethinyl estradiol.

Targeted therapies for tumors that test positive for HER2 include lapatinib and trastuzumab.

 The breast cancer indication of another targeted therapy, bevacizumab, was revoked by the US Food and Drug Administration (FDA) in November 2011 owing to concerns about its effectiveness and safety.

Everolimus, an mTOR inhibitor, was approved by the FDA in July 2012 for use in combination with exemestane to treat postmenopausal women with advanced hormone receptor—positive, HER-2 negative breast cancer after failing treatment with letrozole or anastrozole. The FDA had approved the medication for the treatment of other tumors (eg, advanced renal cell carcinoma, advanced neuroendocrine tumors ofpancreatic origin, and renal angiomyolipoma).

 Results from the phase 3 BOLERO-2 study of 724 patients comparing everolimus plus exemastane versus placebo plus exemastane indicated a plus exemastane group compared with 8 months in the combination therapy group (hazard ratio [HR], 0.45; 

<.0001). The response rates were 1.7% and 12.6%, respectively. Fewer deaths were reported in the combination therapy group. However, patients older than 64 years did not experience any benefit of the combination treatment.

Pertuzumab, an anti-HER2 therapy, in combination with trastuzumab and docetaxel to treat patients with HER2- positive late-stage breast cancer who have received previous anti-HER2 therapy or chemotherapy. Patients in the triple-therapy group demonstrated a median PFS of 18.5 months versus 12.4 months in the group that did not receive pertuzumab (only trastuzumabwas approved by the FDA in June 2012 and docetaxel) (HR, 0.62; 

 Patients receiving the triple therapy had more neutropenia (199 vs 182 patients, respectively), febrile neutropenia (56 vs 30 patients), and diarrhea (32 vs 20 patients) than those receiving trastuzumab and docetaxel.

In July 2012, GlaxoSmithKline announced that it was not pursuing FDA approval of combined use of trastuzumab and its oncology product lapatinib for women with advanced breast cancer.

A total of $10.2 billion was spent in 2009 on breast cancer medications.

This is again the result of the high incidence but also the relatively high price of the treatments. Managed care plans should anticipate even higher costs with the FDA approval of everolimus and pertuzumab, as these agents will be added to existing combination drug regimens.

The monthly cost of everolimus, an oral medication, which will be administered daily, will be approximately $7500 per month.

 The clinical trials indicate that the drug will be administered for at least 4 months and potentially longer.18 This total will be added to the cost of exemastane, which has a price tag of several hundred dollars per month.

Pertuzumab plus trastuzumab will have an even higher cost—pertuzumab will be priced at about $71,000 per year and trastuzumab presently costs $54,000 per year, totaling more than $120,000 per year.

 Both of these medications are specific for HER2-positive breast cancer. The optimal duration of therapy will be at least 6 cycles of therapy.

The duration of treatment can have a major impact on the total cost of therapy. Two different trials for trastuzumab looked at different durations of therapy. The HERA trial compared 1 and 2 years of trastuzumab therapy, with the results indicating that 1 year of therapy is the standard of care.

 Similar results were found in the PHARE study that compared 6 months of trastuzumab therapy with 1 year of therapy.

The results of these studies demonstrated that 1 year of therapy is the optimal duration of therapy for trastuzumab; however, these studies could have had the potential to either reduce the cost of therapy by 50% or increase it by 100%.

Chemotherapy has contributed to the increased life expectancy of patients with breast cancer; however, a cure remains out of reach.

 Determining the cost-effectiveness of therapies for chronic diseases remains a challenge for clinicians, patients, and society—and early-stage breast cancer is fast coming to be considered a chronic disease.

Cost-utility evaluations of trastuzumab have yielded wide-ranging results, from $29,293 to $127,149 per quality-adjusted life-year (QALY), depending on whether they were receiving monotherapy, trastuzumab plus chemotherapy, or trastuzumab plus endocrine therapy and continuing trastuzumab beyond disease progression. A cost-effectiveness analysis of lapatinib in patients with HER2-positive breast cancer who were receiving lapatinib and capecitabine compared with capecitabine monotherapy alone revealed that the combination therapy was cost-ineffective.

Combining 2 anti-HER2 targeted agents will certainly challenge the metrics of cost-effective therapy. It will be paramount that clinical evidence be available to support such therapy.

EBO: Is genomic tumor testing for breast cancer standard practice today?

At HealthPartners we do our very best to follow the evidence. When practices, such as genomic testing, can make a significant difference in the decisionmaking process for a woman suffering breast cancer, we cover it. Rather than looking at standard of practice as the guiding principle in making these decisions, we prefer to look at standards of evidence.

Unfortunately, there are a great many examples of standard of practice racing ahead of evidence and adding no value to the patient’s care and at times even causing serious harm. The stakes become high when a company proposing a treatment measures its impact in terms of a few weeks but values its role in terms of tens or even hundreds of thousands of dollars.

EBO: Assuming that individual testing of breast neoplasms is not yet universal (and assuming it is something to be attained), what are the key challenges for making this standard practice?

Again, evidence that will carry the day. The other real hurdle is to create a reliable approach to consistent application of evidence-based use of these new technologies. There is wide variation in the practice of medicine that has no explanation. This leads to patient harm and failure to realize the full potential of care innovations.

EBO: According to the Centers for Disease Control and Prevention, breast screening rates have actually fallen among Caucasians in the last decade (to

below 70%), remained stable among African Americans (68%), and actually increased significantly among Asians (to 66%). Is it realistic to expect to attain greater percentages? What type of focused interventions may help?

We can expect higher rates of screening. Part of what we need to do is harmonize the recommendations for screening. The conflicting recommendations coming out over the last several years have created confusion. This confusion can discredit the concept of screening, because it leaves patients with the impression that even the experts can’t reconcile the balance of risks and benefits in a way that is reasonable, simple, and consistent. That does not mean that recommendations should be frozen, but I think the recommendations would gain much greater traction if they were consistent, based on a clear-eyed and consistent review of the evidence, and then implemented in a reliable way.

As for focused interventions, we have had success closing disparities in screening rates by doing whatever we can to eliminate barriers to screening. One effective example is same-day screening for women who come to our clinics (HealthPartners is an integrated care delivery and finance organization). This has led to a significant decrease in the difference in screening rates among the different populations we serve, with the greatest benefit evident in our African American patients.

EBO: Do you believe that HER2 targeted agents may be used in combination in the future? If so, do you think combinations of specialty biologics will be the wave of the future in breast cancer therapy?

 I may sound redundant, but it is the evidence that will drive this, as well. The industry has 2 real big problems to solve. First, the treatment and testing changes need to reflect real innovation that has a more significant impact on outcomes than yet seen. Second, the struggle our society faces with the cost of health and

Breast Cancer: Will Treatment Costs Outpace Effectiveness?

The development of targeted therapies for a variety of tumor types has highlighted a greater need for widespread molecular testing to determine which patients have the mutations that these therapies target, and oncologists throughout the world are trying different approaches to translating such advances into broad clinical practice.

In Germany, the feasibility of a community screening program for patients with non-small cell lung cancer (NSCLC) was explored,

 a strategy that provoked discussion at this year’s annual ASCO meeting.

“High-quality molecular diagnostics and personalized treatment approaches present a significant benefit for patients,” said Thomas Zander, MD, of the University Hospital in Cologne, Germany, during a press conference at which his study was discussed.

“At last year’s ASCO meeting, [studies of] large networks for molecular screening testing were presented which consisted of several highly specialized comprehensive cancer centers spread all over the United States, but it meant that getting access to molecular diagnostics was only available to a minority of patients in this country,” Dr Zander said.

Dr Zander’s study focused on testing patients outside of large academic medical centers. In order to perform the study, researchers established the Network Genomic Medicine Lung Cancer. This network included community hospitals in the Cologne-Bonn region of the country, where approximately 2.5 million residents could potentially receive screening.

In all, 2032 samples from NSCLC patients were collected, the authors reported in their abstract.

The figure included 1782 samples from residents of the Cologne-Bonn region, which investigators estimated accounted for between 60% and 70% of all potential NSCLC samples in the area.

Of these samples, 77% were suitable for molecular testing. Samples of tumors of patients with lung adenocarcinoma— the most common form of NSCLC&mdash;were screened for ALK translocations, mutations in KRAS, EGFR, BRAF, and PIK3CA, and amplification of ERBB2. Squamouscell samples were screened for FGFR1 amplifications (

Forty percent of the samples carried mutations for which targeted therapies have been identified, aiding the community hospitals in providing treatment to these patients. For example, patients with ALK mutations were given crizotinib, and patients with EGFR mutations were given EGFR tyrosine kinase inhibitor treatment. Additionally, patients were also referred to clinical trials based on their genetic profiles that involved the testing of other targeted therapies in development.

Dr Zander said the cost for the screenings ranged from approximately €500 to €1000 per patient ($600 to $1200). In the United States and elsewhere, different models are being used. Panel members commented from their vantage points.

“We’re doing a $35 million philanthropically funded trial where patients are allowed access to molecular diagnostics and information is fed back as clinically actionable, and they’re not charged for it,” said George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts.

“We think that’s important because in the next 5 years we need that landscape to see what’s truly actionable, what’s truly important, and then we feel that we can commoditize the molecular testing,” said Dr Demetri. “I think that’s what you’re seeing across the world.”

In France, the French National Cancer Institute has set up 28 laboratories in public hospitals to test for biomarkers, and all patients with cancer receive free testing for biomarkers such as KRAS, EGFR, and BRAF. However, these clinics are limited to proven biomarkers.

“In France, as soon as it is proven that a targeted agent is active against a disease,  the mutation research is reinforced by the French social security system,” said Caroline Robert, MD, PhD, the head of dermatology at the Institute Gustave Roussy in Paris, France. “The problem is or the mutations that are still in the discovery process, with the agents that are not yet on the market.”

Cost factors are important considerations in molecular screenings, and reimbursement practices vary.

“The problem is who should pay for this,” said James Chih-Hsin Yang, MD, PhD, a professor and director of cancer research at the National Taiwan University in Taipei. “In some of the countries, these mutational tests are paid for by insurance companies, such as in Japan. In some countries, these are non-reimbursable at this moment, but I think as more data are coming in, there [will be] no way to deny the reimbursement.”

Although no universal system of molecular testing or reimbursement exists, studies such as the one Dr Zander presented at ASCO suggest that widespread screening is becoming an increasingly feasible and promising way of treating cancer patients.

“It proves that we can choose the most appropriate targeted therapy for patients, we can enroll patients in the appropriate targeted trials,” said moderator Sylvia Adams, MD, assistant professor in the Department of Medicine at New York University Langone Medical Center in New York City. “There is meaningful outcome when we select patients.”

 Mr. Leach reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.1. Zander T, Heukamp LC, Bos MCA, et al. Regional screening network for characterization of the molecular epidemiology of non-small cell lung cancer (NSCLC) and implementation of personalized treatment. J Clin Oncol. 2012;30(suppl; abstrCRA10529).

Exploring New Ways to Broaden the Reach of Molecular Tumor Testing

It is difficult to overstate how much our ability to study the fundamental molecular profiles within individual tumors has revolutionized our basic understanding of the biology of malignant disease.

Further, this information has clearly identified both the heterogeneity of possible driver mutations and pathways within the cancers of individual patients as well as the large number of possible resistance mechanisms available to permit individual cancers to overcome both traditional cytotoxic and the more “targeted” antineoplastic agents.

However, as interesting as this information may be to cancer biologists, what is far more relevant to cancer patients, their families, and treating oncologists is how such data can be increasingly utilized to favorably mpact clinical outcomes.

The term “precision medicine” has been used to describe the impact of knowledge of the unique molecular changes present in individual tumors to devise a more precise therapeutic strategy for that particular patient.

 The “precision” will hopefully result in both improved efficacy (greater “on-target” effect) and reduced toxicity (less “off-target” effect).

It is relevant to acknowledge here that this process of “precision medicine” is certainly not a new concept. For example, for more than 40 years physicians have used knowledge of the presence (or absence) of estrogen/progesterone receptors in breast cancers to determine if hormonal manipulation (eg, removal of the ovaries, administration of tamoxifen, etc) is an appropriate management strategy for that specific individual.

However, what has changed over the past 10+ years is the number of unique settings where such data are of clinical relevance and the rather remarkable acceleration in the development of such knowledge in additional malignancies.

Consider for a moment the fact that it was less than 2 years ago when the first solid reports appeared identifying the fact that a class of anti-neoplastic agents known as BRAF inhibitors could produce rather spectacular responses in patients with metastatic melanoma whose cancers possessed particular mutations in BRAF.

 However, despite this very short time interval, a recently reported phase III trial has now revealed the clinicalsuperiority (prolongation of time-to-disease progression) associated with combining a BRAF inhibitor with another “targeted” agent shown to influence a common mechanism of resistance to such inhibition compared with treatment with the BRAF inhibitor alone.

So, within a remarkably limited period of time we have gone from a theorized role for the presence of a BRAF mutation in the progression of malignant melanoma

 to the demonstration of the favorable impact associated with administering an inhibitor directed at that mutation

 to a strategy that effectively (at least for a clinically meaningful period of time) interferes with a cancer’s ability to resist the effects of such inhibition of its growth.

The Impact of the Revolution in Genomic Sequencing Technology

Perhaps the single most important factor in propelling this spectacular new era forward has been the stunning advances in the technology associated with sequencing.

 The combined activities of industry and academia have led to a profound reduction in both the time required and costs associated with generating these vitally important data.

Consider the fact that the landmark report of the first completely sequenced human genome less than 2 decades ago required a number of years to accomplish at a cost of several billion dollars. It is estimated that this process can currently be accomplished in a matter of days at a cost of several thousand dollars.

 And both the time required and cost of conducting the sequencing for individual tumor specimens (and corresponding non-malignant tissue in the same individual) will almost certainly decrease in the future.

Viewing the Map Versus Breaking the Code for Individual Cancers

At this point it is essential to acknowledge the fundamental difference between possessing specific sequencing data on individual tumors or even highly detailed knowledge of the differences present within such tumors compared with the corresponding genome of the non-malignant tissue in that individual patient versus actually knowing how to interpret the clinical implications of the findings or how to use the information to develop the most effective therapeutic strategy.

Another possible way to highlight this critically important distinction is to compare obtaining the sequencing data itself (as truly eloquent as this may be) with the simple discovery of a previously hidden treasure map or a secret code. And, as interesting as such events may be, it is only after the map/ code has been correctly interpreted and the treasure found or the code broken that the map/code is of genuine value to its owner(s), just as the successful interrogation of the highly complex genomic data and the discovery of clinical relevance will be required before one can conclude there is true value to the patient associated with this effort.

How long it will take to discover the clinical relevance of these molecular data in particular clinical settings (eg, triplenegative breast cancer, squamous cell lung cancer) or in individual patients in such settings (eg, PI3 kinase mutation in ovarian cancer) and to develop effective therapeutics based on the abnormalities identified remains a critical unknown.

It is clear that it will be increasingly possible to obtain molecular profiles on individual tumors in a highly costeffective manner. Further, with time the essential informatics support will surely be able to analyze/interpret possible clinical implications of unique findings. However, a number of highly relevant questions will need to be addressed to permit the most effective use of this spectacular new technology.

For example, if a molecular abnormality is identified in an individual patient’s cancer that has been associated with the favorable effect of a particular commercially available anti-neoplastic agent but in a different tumor type, is it essential for a clinical trial to be conducted and the results reported before it is possible for patients to be treated with that agent in the new tumor site?

Should third-party payers be encouraged or perhaps even required to pay for such treatment based on the presence of a very specific molecular profile that identifies a potential driver mutation in a tumor where formal regulatory approval for this indication has not occurred? Now add to this query the fact that only a very small percentage of patients with this particular tumor type will possess the abnormality (eg, <2%-5%), making it very difficult (if not truly impossible) to conduct a comparative phase III or even a non-randomized phase II study.

In fact, it is highly likely that the scenario posed above will be very common once whole genome sequencing becomes rather standard in the management of advanced or recurrent cancers. How should the 1% of patients found to have “Mutation X” in “Cancer Y” be managed if the documented presence of “Mutation X” in “Cancer Z” has been shown to be favorably impacted if “Drug A” (US Food and Drug Administration— approved for “Cancer Z”) is administered?

A Novel Clinical Cancer Research Paradigm: “N of 1”

In the opinion of this commentator, the outline of a possible solution to this complex individual patient and societal dilemma can be provided by proposing a paradigm-changing clinical research strategy, called by some “N of 1.”

This strategy requires the outcome data generated following the patient described above (eg, 1% of patients with “Mutation X” in “Cancer Y” treated with “Drug A”) to be collected (with any information identifying the individual completely removed) in a database to be joined with such data obtained from similar patients (again, among that 1% of patients with “Mutation X” in “Cancer Y” treated with “Drug A”) to evaluate the efficacy (or perhaps even unique toxicity) associated with the use of this specific agent in the particular setting.

By combining a number of “N of 1” experiences it should be possible to obtain a reasonable view of the relative or absolute benefits associated with the use of this agent. Depending on the particular setting, the relevant end point could be the objective response rate or progression-free survival (compared with a recognized historical population) in the first 20 or 30 “N of 1” patient experiences.

An additional and quite novel end point to consider would be to use the patient as her/his own control, with the time to disease progression on the current regimen (selected at least in part based on molecular testing) being compared with the time to disease progression on the individual patient’s prior treatment regimen.

Based on a rational view of biological systems there is no reason to believe that the rate of disease progression in an individual tumor should improve/ decrease over time in the absence of a favorable effect of a biologically and clinically active anti-neoplastic program. Thus, if the time to disease progression is longer following the current regimen, compared with the prior regimen, it is reasonable to conclude this outcome must have been due (at least in part) to the effects of the current treatment.

 This novel approach to evaluating efficacy of molecularly based antineoplastic therapy has been employed in at least one previously reported highly provocative clinical trial.

Further, the value of the “N of 1” strategy may be substantially enhanced by a proposal that the overall result of a particular experience will be declared to be “positive” only if a genuinely major favorable outcome is documented.

Thus, in this research scenario, a 10% to 15% objective response rate with responses lasting a median of 2 to 3 months will unlikely be considered an outcome that would justify “further research,” as is often stated in the conclusions of manuscripts describing the results of phase II drug trials in the cancer arena. Rather, in this concept, considering both the likely toxicity and anticipated costs of these treatment strategies, one will be looking for solid evidence of more meaningful clinical activity (eg, minimum 30%-40% objective response rate persisting a median of >5-6 months).

Future advances in anti-neoplastic drug therapy will be increasingly based on knowledge of the relevant driver mutations/pathways in individual cancers. Technological advances will soon make it possible to rapidly, cost-effectively, and routinely examine the molecular profiles of the tumors in individual cancer patients.

However, a new clinical research paradigm will be required to evaluate the effectiveness of therapy when small subsets of patients are being managed with a novel strategy. Finally, serious and unavoidable cost considerations will soon mandate a far higher threshold for new/novel anti-neoplastic strategy to be considered to have produced an outcome of genuine clinical value.

 From Cancer Treatment Centers of America, Philadelphia, PA.

Dr Markman reports that he has received consultancies for advisory boards from Foundation Medicine.

December

Trends in the 2012 Eisai Oncology Digest: Insurance and Cost Obstacles in Cancer Treatment

Strategies to Increase the Value of Colon Cancer Medications

Breast Cancer: Will Treatment Costs Outpace Effectiveness?

Exploring New Ways to Broaden the Reach of Molecular Tumor Testing

Precision Medicine and the Rapidly Approaching Future of Cancer Management

Clinical Pathways: An Evolutionary Approach to Cancer Care

Oncology Enters the Informatics Era

Initial Success, Frequent Recurrence

Is Our Healthcare System Ready to Integrate Cancer Care?

Oncologist Practice Consolidation Continues

On the Horizon for Non-Small Cell Lung Cancer

The Complexity of Covering Off-Label Use for a Multitude of Oncology Regimens

Advanced Prostate Cancer: Therapeutic Sequencing, Outcomes, and Cost Implications