Cancer Treatment and Care: Promising Next Steps

There are more than 1,000 diseases lumped into the diagnosis of cancer, where neoplastic cells divide uncontrollably, invade other tissues, damage DNA and continue replicating new mutated cells. It is estimated that half of all men and a third of women will develop cancer at some point in their lives.¹ Epidemiological evidence shows that more than 1.5 million people will be diagnosed with new cancers in 2011 in the U.S. and more than 500,000 of those will die from the disease.²

Genetic Assessment of Cancer Risk

In the last two decades, more than 50 highly penetrant cancer susceptibility syndromes have been linked to inherited genetic mutations.³ In fact, 5 percent to 10 percent of every case of cancer diagnosed is thought to have a hereditary component. So, it is no wonder that science is looking closely at genetics and genomics as not only a method of individualized targeted therapy, but even as a method for risk assessment and prevention.

Evaluating an individual’s cancer risk against the totality of their family history can prove challenging. But, other than an earlier-than-expected onset of cancer, family history is the best predictor of determining genetic links that may lead to cancer. Patterns of disease transmission can determine whether further investigation is warranted. And, the National Comprehensive Cancer Network, an alliance of top cancer centers, can provide guidelines to help clinicians determine who might be an appropriate candidate for genetic testing.³

Clearly, it is recommended that counseling for a genetics risk assessment be undertaken by one trained in the field. However, while there is no cancer specialty in the field of genetics, most who provide cancer risk assessments are oncologists and geneticists. Other allied health professionals who practice genetic risk assessments are genetic counselors or advanced practical nurses. In some cases, genetic assessments may fall on the primary care practitioner.

Currently, there is a need for more specialists and yet a lack of resources for education and training. Cancer genetic seminars, online courses and the American Society of Clinical Oncology (ASCO) curriculum titled Cancer Genetics and Cancer Predisposition Testing all are available, but registration is limited and the waiting list for such programs can be long. And, even with education and training, it may be impractical if not impossible for one person to effectively counsel a patient in the intricacies of genetics and genomics, as well as a course of treatment.

The success of genetic counseling is evidenced by the increased adherence to surveillance that, in turn, leads to the detection of tumors at an earlier and more treatable stage. As the field of genetics and genomics grows, patients will find a new era of biologists, pathologists and other scientists who are able to deliver a comprehensive picture of overall risk.

Prediction Modeling for Cancer

Predicting cancer’s course from screening to end-of-life care can improve with multivariable prediction modeling, which is becoming well-recognized and -utilized in the field. It is even considered to be more useful and accurate than staging in regard to patient survival for numerous types of cancer. Indeed, a study of physicians’ estimation of life expectancy for near end-of-life cancer patients improved significantly with prediction modeling over subjective predictions alone.⁴ And, insurance companies may be more likely to approve genetic testing if probability models indicate a high risk in the context of overall family history.

There are numerous well-regarded prediction models for a whole host of cancers from the Gail Model for breast cancer prediction (www.cancer.gov/bcrisktool) to the Kattan Nomogram for the risk of reoccurrence of prostate cancer after a radical prostatectomy (www.nomograms.org) to the ACCENT Model for the value of adjuvant therapy for colon cancer patients (www.mayoclinic.com/calcs/colon/index-ccacalc.cfm). However, clinicians need to be aware of which prediction model they are choosing of the many thousands available, as many have not been independently validated.⁴

It should be noted that today’s electronic health records (EHRs) are somewhat limited in the ability to pull patient risk assessment and test results into prediction models, as well as incorporating that information into patient care.⁴ It is expected that newer generations of EHRs should fare better in this regard.

Genes and Genomes — A Growing Field of Study

Genomics research is progressing rapidly, and the impact on cancer cannot be overstated. While genes and genomes do not need to be fully understood to effectively identify cancer risk, they do need to be understood to develop treatments to combat the disease. A lack of understanding is a limiting factor in today’s ability to produce cancer-preventing drugs.

Cellular metabolism. Drugs targeting metabolic enzymes in the treatment of cancer are proving to be successful. However, finding a therapeutic window between normal and proliferating cancer cell metabolism is a challenge, as the metabolic requirements are the same. All proliferating cancer cells divert nutrients away from normal cells, and most of that diversion is to support biosynthesis. Another challenge is that different types of cancer use differing amounts of nutrients in different manners. Understanding how this nutrient rebalancing works is the key to redirecting and rewiring the pathways away from cancer cells as a means for therapy because there are different needs for each type of cancer, as well as for metabolism and DNA synthesis.

The idea of metabolism affecting cancer cell proliferation is rooted in the knowledge that obesity, hyperglycemia and insulin resistance are associated with increased cancer risks, possibly by activating signaling pathways that promote cell growth. Patients who are on the anti-diabetic drug metformin have shown fewer cancer-related deaths; however, this is not the case with other blood glucose-controlling drugs. This, then, begs the question of whether the drug is targeting the cancer directly or indirectly via lowered blood glucose or insulin-related growth factors. Metformin in high doses is also toxic to cancer stem cells. Preliminary findings suggest women who take the drug while undergoing chemotherapy have a better response, and clinical trials for women with breast cancer are in the planning stages to determine who might best benefit from metformin and whether the drug could be used as a chemo prevention for those at high risk.⁵

It is likely that drugs targeting metabolic enzymes will enter the clinical trial stage within the next few years because results in preclinical settings are encouraging in two approaches: 1) they limit the macromolecular synthesis needed for cell growth, and 2) they limit the supply of nutrients to the cell to impair cancer growth.

Biological response modifier therapy. When natural or laboratory manufactured monoclonal therapies are introduced, the hope is the body will use them like natural antibodies to fight tumor target antigens (this process is known as apoptosis). The first monoclonal antibodies were approved in the late 1990s and are proving effective for treating breast and lymphoma cancers. Today, others are being studied.

A small study is showing promise for leukemia patients who received re-engineered versions of their own T-lymphocyte cells to boost the immune system. The patients who had chronic lymphocytic leukemia (CLL) and had been previously treated using other methods had their T cells removed and modified with a virus to enable new genes that target B-lymphocyte cells. After reinjection into the body, the cells began killing CLL tumor cells and, within weeks, the tumor had been “blown away,” said one of the study authors. Another small-scale study will begin shortly, and if successful, a large-scale study is anywhere from five to 10 years away. 6 Targeted therapies leading to apoptosis are a growing field.

Thirty years after the discovery of the p53 tumor suppressor protein, encoded in the TP53 gene, scientists are looking at the effectiveness of drugs in targeting the tumor cell and at p53 as a predictive factor in the diagnosis and spread of cancer. TP53 is often mutated with cancer, clustering at a hot spot and leading to one of three alterations of p53 at the DNA binding domain. It appears that all cancers have a defective p53 either by TP53 mutation or altered pathway of p53, and the effects of a mutated p53 differ depending on which cancer cells are affected. Scientists are working to define p53 molecular profiles in hopes of having more clearly defined disease predictors and treatments.⁷

Two drugs have been shown effective in activating wild-type p53 proteins in tumors: Nutlin-3, which induces accumulation of p53 and Mdm2, and RITA, which binds and stabilizes p53 while suppressing Mdm2. PRIMA-1 is one of several drugs that can restore wild-type p53 activity; however, at present the exact mechanism by which this happens is unknown. These drugs are ready to move into clinical trials, and it is hoped that in 10 years, the aim of personalized medicine will be closer.⁷

The immune system’s T cells are a frequent focus of clinical studies in treating cancer, and the dream of reprogramming immune cells to target cancer cells has potential. After a clinical trial was stopped in 2010 due to the death of two study participants, researchers at the University of Pennsylvania Medical Center have successfully engineered a T cell to recognize the CD19 protein on the surface of the cancerous cell, as well as on B cells. This engineered T cell, in combination with an antibody to target the cancer and part of a receptor that increases the T-cell response, has shown a 1,000-fold proliferation, much of which was still present after six months. In their small study, two of the participants were in complete remission and a third was showing marked improvement. Because the study group was so small, the results are preliminary but clearly promising.⁸

A new class of therapy called PARP inhibitors is showing promise in killing cancer cells in those with defective BRAC1 and 2 genes who have cancers of the breast, ovary and prostate. Scientists also are looking at the possibility that this treatment may work in those without the mutation. PARP-1, or poly (adenosinediposphate-ribose) polymerase, allows cancer cells to repair DNA damage, including damage made by cancer treatment. And, these PARP inhibitors can make cancerous cells more sensitive to treatment, prevent the repair and cause the cell’s death.

There are numerous PARP inhibitors under review and two in particular are causing excitement — olaparib (AstraZeneca) and BSI201 (BiPar Sciences) — because of their “synthetic lethality” in killing cancer cells while not disturbing healthy cells.⁹

A new drug, recently approved by the U.S. Food and Drug Administration, Adcetris (brentuximab vedotin), is an antibody-drug conjugate, much stronger than “naked antibodies,” that can directly target CD30 proteins on lymphoma cells and kill them.It is hoped that the direct target will prevent toxicities from methods like chemotherapy from being transported via the bloodstream through the body. A recent study showed 74 percent of the 102 study participants with Hodgkin’s lymphoma saw a partial or complete remission, and 94 percent saw their tumors shrink. There are now about 25 additional antibody-drug conjugates in ongoing trials, and it is expected that more variations of this therapy will soon be on the market.¹⁰

Stem cell therapy. Cancer stem cells, making up just 1 percent to 3 percent of cells in a tumor, are the driving factor in a tumor’s growth. First identified in 2003, cancer stem cells have been isolated in breast cancer, tumors of the neck and head, an aggressive brain cancer called glioblastoma and in the pancreas. Cancer stem cells look just like regular cancer cells, so they are identified by certain proteins that regular cancer cells do not have.

As the ability to better isolate and identify cancer stem cells improves, physicians will have a better understanding of a patient’s risk for developing cancer, as well as new targeted therapies to treat it, potentially killing cancer stem cells in the original tumor before it has an opportunity to spread.¹¹

Self-Management and Palliative Care

Providing the best quality of life for a cancer patient, no matter where they are in their diagnosis and treatment continuum, is a priority for both caregivers and patients, and is being offered at more and more hospitals, outpatient clinics and in-home settings.

Thanks to early detection, diagnosis and successful treatments, some can manage cancer like a chronic illness, rather than an acute disease. Family members, patients, oncologists and primary care providers can work together via guidance of the American Cancer Society’s Chronic Care Model (CCM) to formulate a self-management plan that ensures the right tools are available for management and comfort long after traditional treatments have ceased. This includes forming relationships with those who can help, improving skills in problem-solving, decision-making and the ability to take decisive action with regard to healthcare, emotional care and comfort care. Numerous studies have shown the validity and usefulness of self-management through all stages of cancer and survivorship and even end of life.

The CCM includes six steps: self-management support, delivery system design, decision support, clinical information systems, healthcare organizations and the identification and use of community resources. 12 Mutually agreed-upon care plans are the goal, allowing for patients to feel good about their plan and their ability to have some control over the outcome, even if the outcome is based on emotion or comfort. One major limitation that providers need to keep in mind is a common language that is understandable to the patient and family. Another limitation is the patient’s willingness to accept their role in self-management and to take charge. Expectations of providers often outweigh the patient’s ability or motivation.

Self-management and palliative care interventions are most successful for the patient when incorporated early. The American Society of Clinical Oncology has set a goal of incorporating palliative care into cancer care practices by the year 2020.

Better Treatments Moving Forward

The search for better cancer treatments continue to move forward at a rapid pace as scientists better understand the disease and how therapies target it. Of course, better treatment also encompasses a patient’s level of comfort and security of their situation and their ability to impact it in numerous ways. As improvements in the scientific process move forward, as well as improvements in palliative care, the entire experience for the patient will be changed for the better — from identification of risk to early diagnosis, improved and targeted therapies and the informed decision-making continuum for all involved.