 that are known to drive subsets of lung cancer are also present in colorectal cancer according to a recent study in 

. It is now hoped that the drugs targeting ALK and ROS1 can also be applied to treat patients with colorectal cancer (CRC).

Dara Aisner, MD, PhD, an investigator at the Colorado University (CU) Cancer Center and a molecular pathologist at the CU School of Medicine, and colleagues used fluorescence in situ hybridization (FISH) to test for the oncogenic gene arrangements in 236 tumor samples. Samples were collected from patients who had previously been studied as part of a clinical trial in Australia that looked at a particular chemotherapy combination in metastatic colon cancer and had histologically confirmed colorectal adenocarcinoma. From each patient, three tumor tissue cores were taken and distributed in 10 blocks, making up a 12x8 grid of cores on each slide. Thirtynine of the patients were sampled twice, and three were sampled three times for quality control.

Two cases (0.8%) showed FISH patterns that were consistent with 

 signals. One case (0.4%) exhibited a pattern consistent with 

 rearrangement and also had predominantly single 3’

 signals. Seven cases (3%) showed the atypical pattern 3’ALK doublets (3’/5’/3’

 were also identified, including 25 cases with 3’/5’ fusion ALK doublets (10.6%), and 12 cases each (5.1%) with 3’ROS1 doublets (3’/5’/3’

According to the study report, the researchers were surprised to find marked intratumoral heterogeneity for both 

 rearrangement status. Finding all four combinations of 

 status throughout the specimen was especially unexpected, as was the identification of a region of high-grade dysplasia harboring both molecular alterations. Several other studies have shown that the 

 mutation is an early event in colorectal carcinoma tumorigenesis.

“This is one of man y evolving studies demonstrating that while well described molecular alterations might be more common in a par ticular tumor type, to assume that they are exclusive to a single tumor type underestimates the diversity of biology,” Aisner explained in an interview with 

. “It is r eally only through sampling relatively large numbers of cases that we can f ind rare events, and in my mind, this further suggests that largescale evaluation for genomic alterations is an important part of the future of both scientific study and medicine. For colorectal carcinoma specifically, this identifies a rare but potentially targetable alteration that could provide treatment benefit for patients.”

Aisner said the researchers’ ultimate goal with this study is “to identify new targets for therapy for CRC patients, as well as patients with other tumor types.”

Aisner DL, Nguyen TT, Paskulin DD, et al. ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers [published online ahead of print December 2, 2013]. 

Articles

Gene rearrangements ALK and ROS1 that are known to drive subsets of lung cancer are also present in colorectal cancer according to a recent study in Molecular Cancer Research.

ALK and ROS1 Lung Cancer Oncogenes May Also Drive Colorectal Cancer

Genmab, the publicly traded, international biotechnology company, has an oncology pipeline that focuses on two classes of drugs: naked antibodies and antibody drug conjugates (ADCs). Its products are being developed in more than 70 active clinical studies, and its lead agent, ofatumumab (Arzerra), was launched after only 8 years in development. Other products undergoing clinical investigation at Genmab include the antibody daratumumab and the ADC HuMax- TF-ADC.

Results from a recent phase III study presented at the 55th American Society of Hematology Annual Meeting in New Orleans, Louisiana, demonstrated improved clinical outcomes when ofatumumab was added to chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL). The data showed that median progressionfree survival, overall response rate, complete response rate, and the treatment-free period were all superior with the addition of ofatumumab to chlorambucil compared with chlorambucil alone

Ofatumumab is a monoclonal antibody that targets an antibody determinant (epitope) that’s found on the B-lymphocyte antigen CD20. Ofatumumab attaches to the CD20 molecule, which is found on the surface of B cells. B cells become cancerous in CLL. The CD20 molecule is found on over 90% of B-cell lymphomas, as well as other lymphoid tumors of B-cell origin.

Genmab and GlaxoSmithKline comarket ofatumumab. It is approved for patients with CLL who are refractory to fludarabine and alemtuzumab. The FDA recently granted priority review to a supplemental Biologics License Application for ofatumumab in combination with an alkylator-based therapy in treatment-naïve CLL patients who are not eligible for fludarabine-based therapy. A decision on the indication will be made on or before April 19.

The most common adverse reactions reported with ofatumumab are neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions seen are infections (including pneumonia and sepsis), neutropenia, and pyrexia.

Ofatumumab is undergoing investigation in other oncology and autoimmune diseases including follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), Waldenström’s Macroglobulinemia, pemphigus vulgaris, and relapsing-remitting multiple sclerosis.

Another monoclonal antibody in Genmab’s pipeline is daratumumab, a human CD38 antibody that is undergoing investigation in multiple myeloma. The drug could also have potential in other hematological malignancies in which CD38 is expressed, including DLBCL, CLL, acute lymphoblastic leukemia, acute myeloid leukemia, follicular lymphoma, and mantle cell lymphoma.

The FDA has granted daratumumab Fast Track designation as a potential treatment in patients with multiple myeloma. It is indicated in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and IMiD.

HuMax-TF-ADC is an ADC that targets tissue factor, a protein involved in tumor signaling and angiogenesis. The conjugate is highly expressed in solid tumors, with rapid internalization. These characteristics make it a viable target for an ADC approach. It is being developed in collaboration with Seattle Genetics. HuMax-TF-ADC is undergoing a phase I dose escalation trial to treat multiple solid tumors.

Genmab, the publicly traded, international biotechnology company, has an oncology pipeline that focuses on two classes of drugs: naked antibodies and antibody drug conjugates

Genmab Focuses Oncology Research on Monoclonal Antibodies

Administering chemotherapy concurrently with androgen deprivation therapy (ADT), rather than saving cytotoxic treatment until after progression, improves overall survival for men with hormone-sensitive metastatic prostate cancer, a study has demonstrated.

Patients who concurrently received ADT and the chemotherapy drug docetaxel had a 3-year survival rate of 69%, as compared with a 3-year survival rate of 52.5% for men in the same population who received ADT alone, investigators found in study E3805.

“The results of this study are practice-changing,” said lead investigator Christopher Sweeney, MBBS, clinical director of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. “We have strong scientific evidence that patients with the most advanced metastatic prostate cancer benefit from the early addition of docetaxel to ADT and not waiting until the cancer has progressed on hormonal therapy. The findings of this study are important both for improving the clinical care we deliver now and in designing new clinical trials as we strive to further improve the lives of men with metastatic prostate cancer.”

“Additionally, these findings are an example of how combining two approved and available treatments can produce a significant improvement in clinical outcome,” said Jeff Abrams, MD, clinical director of the Division of Cancer Treatment and Diagnosis at the National Cancer Institute (NCI), which sponsored the study.

The positive results were released prior to the study’s close after a planned interim analysis, at the recommendation of the independent Data and Safety Monitoring Committee overseeing the trial, according to a written statement about the findings released by the National Institutes of Health, which includes the NCI.

In the study of 790 men with metastatic prostate cancer, patients received either ADT alone or ADT with docetaxel every 3 weeks for a total of 18 weeks. In addition to recording an overall survival benefit, investigators observed that men who had a high extent of metastatic disease at the start of treatment were the most likely to benefit from the drug pairing, with a 3-year survival rate of 63.4%. Men with a high level of metastatic disease who took ADT alone had a 3-year survival rate of 43.9 %, according to the statement.

The researchers stratified the subgroups by determining at the study’s outset whose disease had spread to major organs such as the liver and/ or resulted in four or more bone lesions. Further follow-up will be performed on trial participants with less extensive metastatic disease, in order to determine their response to the treatment combination, the statement said.

In men with metastatic prostate cancer, the typical treatment sequence is initial ADT; then, after progression, newer hormonal therapies such as abiraterone and enzalutamide; and finally, after further progression, chemotherapy, Sweeney told 

In the past, physicians have paired chemotherapy with ADT before a patient developed castration-resistant prostate cancer only on an “ad hoc basis,” and it was considered “off protocol,” Sweeney said. Based on the data generated in study E3805, physicians now have a rationale for using the pairing more regularly, Sweeney said. The NCI statement cautioned, however, that doctors should restrict their use of this combination to patients with high-extent metastatic prostate cancer who are candidates for treatment with docetaxel, since the chemotherapy is associated with some toxicities.

Since docetaxel has already been approved by the FDA for the treatment of late-stage prostate cancer, and ADT is also an approved therapy, physicians don’t have to wait for government approval before using the new strategy, Sweeney noted. “In the US, seeing as it is approved, I think the only barrier will be insurance approval,” he said.

Sweeney said that he and the study’s other investigators will present their data at scientific meetings and publish it in peer-reviewed journals this year in order to inform the oncology community, encourage their use of the new strategy, and seek the inclusion of the drug pairing in treatment guidelines for this patient population.

National Institutes of Health. NIH-funded study shows increased survival in men with metastatic prostate cancer who receive chemotherapy when starting hormone therapy. NIH website. http://1.usa.gov/1cP1Eac. Published December 5, 2013. Updated December 6, 2013. Accessed January 7, 2013.

Administering chemotherapy concurrently with androgen deprivation therapy (ADT), rather than saving cytotoxic treatment until after progression, improves overall survival for men with hormone-sensitive metastatic prostate cancer

Adding Chemotherapy to ADT Improves Survival in Metastatic Prostate Cancer

Some researchers believe the uncontrolled cell division that defines cancer is a characteristic of damage that occurs at the telomeres, the protective caps at the end of the chromosomes that contain the cell’s genetic material. Telomerase is a naturally occurring enzyme that helps to maintain the telomeres during cell division. The enzyme consists of an RNA template, which binds to the telomere, and a catalytic subunit with reverse transcriptase activity, which adds a specific DNA sequence at the ends of the chromosome. Geron Corporation’s anticancer research strategy is to focus on telomerase activity through the continuing clinical development of the telomerase inhibitor imetelstat.

The company presented data at the 55th Annual Meeting of the American Society of Hematology (ASH) demonstrating imetelstat’s activity in myelofibrosis. In that trial, nine of 22 patients had objective responses, four of which were complete remissions. Two-thirds of the patients met criteria for an objective response or had a >50% reduction in white blood cell count. The findings were presented by Ayalew Tefferi, MD, a hematologist at the Mayo Clinic in Rochester, Minnesota.

These findings followed on the heels of updated clinical results from a phase II proof-of-concept trial of imetelstat in essential thrombocythemia. Those trial results were presented at the 18th Annual Congress of the European Hematology Association. The data showed a 100% response rate in patients, including 16 complete responses. Those results added to a favorable report at the 2012 ASH Annual Meeting involving fewer patients and a shorter duration of follow-up.

The rationale for Geron Corporation’s focus on inhibiting telomerase in cancer is the belief that inhibiting the enzyme may limit the proliferative capacity of malignant cells. Geron researchers have observed in various in vitro and rodent tumor models that inhibiting telomerase results in telomere shortening and arrests uncontrolled malignant cell proliferation and tumor growth. Many blood-based cancers are known to arise from malignant progenitor cells in the bone marrow, providing a strong rationale for potential treatment with a telomerase inhibitor.

The number of divisions that occur during cell division is regulated by telomere length. Each time a cell divides, the telomeres shorten. Eventually, they shrink to a critically short length, and as a result the cell either dies by apoptosis or stops dividing and senesces. In contrast to normal cells, most cancer cells have relatively short telomeres and exhibit high levels of the enzyme telomerase.

Imetelstat is a short, modified, lipid-conjugated 13-mer oligonucleotide that is complementary to and binds with a high affinity to the RNA template of telomerase. This high affinity characteristic directly inhibits telomerase activity. The compound has a proprietary thio-phosphoramidate backbone, which provides resistance to the effect of cellular nucleases, thus conferring improved stability in plasma and tissues.

In general, commercial development of telomerase inhibitors has been slow because small molecules undergoing development have lacked potency and specificity. However, imetelstat has made some significant clinical progress.

Some researchers believe the uncontrolled cell division that defines cancer is a characteristic of damage that occurs at the telomeres, the protective caps at the end of the chromosomes that contain the cell's genetic material. 

Geron Looks to Break Through With Telomerase Inhibitor Imetelstat

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Little is known, however, about how these factors may impact the survival of patients with established colorectal cancer, many of whom seek to understand which diet and lifestyle behaviors—beyond standard treatment with surgery, chemotherapy, or radiation&mdash;will improve their outcome.

Following on the recommendation of an American Cancer Society consensus panel highlighting the urgent need for more research on the effect of nutrition and physical activity on the prognosis of cancer survivors, the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute has developed an innovative, crossdisciplinary, translational research program to elucidate the role of diet and lifestyle behaviors in the survival of colorectal cancer patients.

Among the factors that we have identified as being potentially protective are exercise,

 and vitamin D status. For vitamin D, in particular, abundant data from the laboratory as well as epidemiologic studies support a potential antineoplastic effect. Efforts are underway to further understand the biologic mechanisms by which vitamin D may contribute to colorectal cancer pathogenesis and the potential clinical impact of supplementation on patient management.

The hypothesis that vitamin D status is related to colorectal cancer has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of the vitamin D receptor (VDR)

 which converts plasma 25-hydroxyvitamin D

[25(OH)D] into 1,25-dihyroxycholecalciferol [1,25(OH)2D], the active metabolite. Binding of VDR by 1,25(OH)2D leads to transcriptional control of target genes, resulting in induction of differentiation and apoptosis,

Vitamin D inhibits growth and promotes differentiation of colorectal cancer cell lines and xenografts.14,18-21 Rats maintained on a diet enriched in 1,25(OH)2D develop fewer intestinal tumors and metastases compared to control animals.

 Treatment of ApcMin mice with vitamin D or a synthetic analog reduces the size of intestinal adenomas,

 and epidemiologic data also suggest that vitamin D plays a role in colorectal cancer carcinogenesis. A meta-analysis of nine prospective studies showed that individuals with higher plasma levels of 25(OH)D, the best indicator of vitamin D status, have a significantly reduced risk of developing colorectal cancer.

The influence of vitamin D on survival of patients with established colorectal cancer remains uncertain, however, and we conducted several studies to try and address this knowledge gap.

		Figure. Plasma 25(OH)D and Survival in 304 Colorectal Cancer Patients (NHS/HPFS)

		Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity. (Ng K, et al. 

Among 304 colorectal cancer patients in the Nurses’ Health Study (NHS) and the Health Professionals Follow- Up Study (HPFS) who had blood samples available, we measured 25(OH)D concentrations prior to colorectal cancer diagnosis and assessed for a correlation with survival. We found that higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (

 This finding was subsequently confirmed in another study of 1017 colorectal cancer patients in the NHS and HPFS, where higher postdiagnosis vitamin D scores calculated from known clinical determinants of vitamin D status were found to be significantly associated with improved cancer-specific (adjusted hazard ratio [HR] = 0.50; 95% CI, 0.26-0.95; 

 trend = .02) and overall survival (HR = 0.62; 95% CI, 0.42- 0.93; 

 trend = .002).28 In subgroup analyses, the benefit of higher plasma 25(OH)D seemed greater in stage III and IV patients than stage I and II (adjusted HR = 0.40 vs 0.90, respectively, comparing extreme quartiles).

To further test the benefit of vitamin D in advancedstage colorectal cancer, we conducted an analysis of plasma 25(OH)D levels drawn at study registration in 515 stage IV colorectal cancer patients enrolled in a completed, National Cancer Institute-sponsored clinical trial of palliative chemotherapy (North Central Cancer Treatment Group N9741).

 We found extremely low circulating concentrations of 25(OH)D in this population, with a median level of 20.0 ng/ mL. Indeed, only 10% of the cohort had levels ≥33 ng/mL, the threshold believed to be required for a protective effect of vitamin D on colorectal cancer risk.

 These low levels of plasma 25(OH)D are especially concerning in light of laboratory and epidemiologic evidence that higher levels are associated with improved outcome.

Given the prevalence of vitamin D deficiency and insufficiency among metastatic colorectal cancer patients, the hypothesis-generating finding of a greater benefit of vitamin D among advanced-stage patients, and preclinical studies revealing potential synergy between vitamin and cytotoxic drugs such as platinums

 we are now translating our observational findings into a clinical intervention for patients.

We are currently conducting a multicenter, randomized, blinded, placebo-controlled phase II study of FOLFOX + bevacizumab in combination with either standard-dose vitamin D

 at 400 IU/day versus higher- dose vitamin D

 at 4000 IU/day in previously untreated, stage IV colorectal cancer patients, with a primary endpoint of progression-free survival (ClinicalTrials.gov identifier NCT01516216). Approximately 120 patients will be enrolled on the study, and accrual is actively ongoing at multiple centers across the United States. Serial plasma and DNA samples and archival tumor tissue will be collected from all patients and banked for future correlative studies.

These correlative studies will be critical to fully understanding the role of vitamin D in colorectal cancer pathogenesis. Despite the abundant laboratory and observational data discussed above, the exact molecular and genetic mechanisms underlying vitamin D’s antineoplastic effects are unknown. Consequently, an entire project in our Dana-Farber/Harvard Cancer Center SPORE (Specialized Programs of Research Excellence) in gastrointestinal cancer is devoted to investigating the transcriptional targets of VDR in cell lines, xenograft mouse models, and human primary colon tumor samples. Moreover, multiple analyses of germline polymorphisms in vitamin D pathway genes are ongoing to determine if genetic variation significantly affects response to vitamin D supplementation as well as colorectal cancer patient outcome.

The potential to modulate the progression of colorectal cancer through nutritional and lifestyle factors is very real but insufficiently studied, and a clinical and translational approach that steps beyond purely observational studies is required to establish causality. In addition, elucidation of a biological mechanism underlying these clinical findings would enhance the acceptability of vitamin D as critical for cancer prevention and treatment.

In this era of expensive and often toxic antineoplastic drugs, vitamin D represents an attractive treatment option for patients and oncologists with respect to both safety and cost, and improving understanding of vitamin D in colorectal cancer could potentially shift the paradigm in managing this disease.

			Meyerhardt JA, Giovannucci EL, Ogino S, et al. Physical activity and male colorectal cancer survival. 

			Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. 

			Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer diagnosis. 

			Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. 

			Meyerhardt JA, Catalano PJ, Haller DG, et al. Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. 

			Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. 

			Chan AT, Manson JE, Feskanich D, Stampfer MJ, Colditz GA, Fuchs CS. Long-term aspirin use and mortality in women. 

			Meggouh F, Lointier P, Saez S. Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normal mucosa. 

			Vandewalle B, Adenis A, Hornez L, Revillion F, Lefebvre J. 1,25-dihydroxyvitamin D3 receptors in normal and malignant human colorectal tissues. 

			Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. 

			Vandewalle B, Wattez N, Lefebvre J. Effects of vitamin D3 derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: possible implication of intracellular calcium. 

			Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. 

			Scaglione-Sewell BA, Bissonnette M, Skarosi S, Abraham C, Brasitus TA. A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. 

			Iseki K, Tatsuta M, Uehara H, et al. Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. 

			Fernandez-Garcia NI, Palmer HG, Garcia M, et al. 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. 

			Lamprecht SA, Lipkin M. Cellular mechanisms of calcium and vitamin D in the inhibition of colorectal carcinogenesis. 

			Evans SR, Shchepotin EI, Young H, Rochon J, Uskokovic M, Shchepotin IB. 1,25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model. 

			Shabahang M, Buras RR, Davoodi F, et al. Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3. 

			Eisman JA, Barkla DH, Tutton PJ. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. 

			Giuliano AR, Franceschi RT, Wood RJ. Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: effect of cellular differentiation. 

			Zhao X, Feldman D. Regulation of vitamin D receptor abundance and responsiveness during differentiation of HT-29 human colon cancer cells.

			Beaty MM, Lee EY, Glauert HP. Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high fat diets. 

			Huerta S, Irwin RW, Heber D, et al. 1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse. 

			Zheng W, Wong KE, Zhang Z, et al. Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. 

			Larriba MJ, Ordonez-Moran P, Chicote I, et al. Vitamin D Receptor Deficiency Enhances Wnt/beta-Catenin Signaling and Tumor Burden in Colon Cancer. 

			Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. 

			Ng K, Meyerhardt JA, Wu K, et al. Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. 

			Ng K, Wolpin BM, Meyerhardt JA, et al. Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer. 

			Ng K, Sargent DJ, Goldberg RM, et al. Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741. 

			Gorham ED, Garland CF, Garland FC, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. 

			Cho YL, Christensen C, Saunders DE, et al. Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. 

			Moffatt KA, Johannes WU, Miller GJ. 1Alpha,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. 

			Kulkarni AD, van Ginkel PR, Darjatmoko SR, Lindstrom MJ, Albert DM. Use of combination therapy with cisplatin and calcitriol in the treatment of Y-79 human retinoblastoma xenograft model. 

			Light BW, Yu WD, McElwain MC, Russell DM, Trump DL, Johnson CS. Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system. 

			Liu G, Hu X, Chakrabarty S. Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and survivin and promotes cellular sensitivity to 5-FU.

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer.

Examining the Role of Vitamin D in Colorectal Cancer Survival

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

 takes a particularly important meaning this year, as Jan 1, 2014, is now a landmark date in the history of US healthcare with the implementation of the Affordable Care Act (ACA), also referred to as 

, which was passed into law in March 2010.

Almost 50 years have passed since the last big change in US healthcare came with the establishment of Medicare in 1965. However, the complexity and scope of the ACA is truly unprecedented given both the number of players (patients, physicians, hospitals, pharmacies, pharmaceutical industry, diagnostic companies, employers, and insurance providers) and the extensive medical progress since the implementation of Medicare, which has translated into much more complex and costly medical care.

The ACA was enacted with the goals of increasing the quality and affordability of health insurance. The law requires coverage through either an employer, Medicare, expansion of Medicaid (younger adults), or through personal mandate (or else financial penalty). It also requires minimum standards for health insurance policies and increases coverage: no coverage denial for preexisting conditions, no lifetime cap, no/lower copay for screening and preventive medicine, and children up to age 26 can be included under their parents’ coverage. The ACA will mostly be financed by increased taxes and decreased Medicare reimbursement to hospitals.

Despite more than 3 years of preparation since the law passed (with numerous attempts to repeal it) and putting politics aside, the reality of implementation of the ACA is and will be—as expected&mdash;facing numerous serious challenges. Appropriate concerns have emerged over the last few months, including difficulties for individuals trying to sign up (horrendous ACA website stories), challenges in the insurance exchanges from increased premiums, the inability to keep one’s previous plan, and forced loss of access to individuals’ existing healthcare providers. Meanwhile, the controversy about the reluctance of some states to even support Medicaid expansion adds to the growing anxiety.

Although to this day only a minority of Americans—much fewer than predicted&mdash;have signed on for new health plan coverage, it remains totally unclear in this transition phase how things will unfold practically. A number of justified concerns persist on how this is going to translate into doctors’ offices, from confusion about coverage, increased premiums and/or deductibles, to increased medical spending, and eventually poorer coverage and worsening of quality of care.

That being said, no one would (or could) deny that the current course of spending for healthcare in the United States is not sustainable. The Medicare Sustainable Growth Rate (SGR) is currently used by the Centers for Medicare and Medicaid Services to frame federal healthcare spending. Generally, this method aims to ensure that the yearly increase in the expense per Medicare beneficiary does not exceed the growth in gross domestic product. Though it is necessary to control healthcare costs, adjustments of SGR (hence, of reimbursement to physicians) occurred for many years solely through temporary remedies, keeping physicians and patients in a constant state of uncertainty, and this is also not sustainable.

At the end of 2013, the government issued a new temporary relief with a 3-month, 0.5% payment increase (the first since 2010) in lieu of the 24% cut in Medicare reimbursement initially scheduled for January 2014. A reliable payment system will be essential to support the enforcement of all these changes at a time when physicians are already facing pressure related to the electronic health record mandate and the upcoming new ICD- 10 coding implementation, on top of the uncertainties related to the ACA itself.

Amid all these controversies and growing concerns, public support for the law has dropped to a record low and is the subject of intense politics. I believe, however, that it is important that we do not lose track of the main goal, which is improving the health of all Americans.

Given the stakes, one should view this as an opportunity for greater and more commendable changes by focusing more on quality, outcome, and accountability, instead of just the possibility of rationed care though an increasingly complex and cumbersome regulatory and bureaucratic environment.

Being an oncologist, it appears rather obvious to me that cancer provides a perfect platform to develop a new and requisite model that could be an example of a move toward transformative care in medicine. A number of converging forces are undeniably reshaping oncology: costly medicine (with the bulk of expenses still spent in the palliative setting), an aging population (increasing cancer incidence), and better outcomes due to better therapies. Further, the molecular diversity of cancer will affect drug development and clinical trial design (targeting patient populations based on molecular rationale), which in turn could reduce the cost of drug development and hopefully the eventual cost of the drugs. Together with the availability of high-throughput diagnostic technologies (sequencing and other genomics approaches), a natural shift toward personalized or precision medicine in oncology is palpable and has already started.

More than ever, it will be particularly important in oncology to all work together to bring innovation and novel therapies to patients. The ACA needs to address the issues related to clinical trial support and access for patients while easing the burden of investigators subjected to an increasingly cumbersome regulatory environment. The enormously complex ACA has already been amended multiple times and is likely “not final”; let’s hope appropriate changes can and will be made to support innovation and continued progress, as knowledge remains the best medicine.

Meanwhile, proactively involving physicians in responsible initiatives to control cost and improve outcomes appears more constructive and promising. Moving toward bundled care with relevant patients’ stratification and innovation is the future. The answer is to view this as an opportunity to be transformative in oncology and medicine at large: Would anyone not want rationale care versus coercively rationed care?

Change of this scale is never easy, but with the well-being of our society at stake, as well as the future of medicine and innovation leadership in our country, the ACA needs to address, support, and embrace all the exciting changes happening in cancer care and medicine as a whole.

The classic saying Have a Happy and Healthy New Year takes a particularly important meaning this year, as Jan 1, 2014, is now a landmark date in the history of US healthcare with the implementation of the Affordable Care Act (ACA), also referred to as Obamacare

January 2014 | Oncology & Biotech News

ALK and ROS1 Lung Cancer Oncogenes May Also Drive Colorectal Cancer

Genmab Focuses Oncology Research on Monoclonal Antibodies

Adding Chemotherapy to ADT Improves Survival in Metastatic Prostate Cancer

Geron Looks to Break Through With Telomerase Inhibitor Imetelstat

Examining the Role of Vitamin D in Colorectal Cancer Survival

Can We Hope for the Best From the Affordable Care Act?