Scientists now know a lot more about the genetic landscape of head and neck cancer and hope that eventually this knowledge will lead the way to new therapies, according to Aaron D. Tward, MD, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. Tward described findings of recent collaborative research on the topic at the 2012 Chemotherapy Foundation Symposium.

For this research, Tward, also with the Department of Otology and Laryngology at Harvard Medical School and a clinical fellow in those specialties at the Massachusetts Eye & Ear Infirmary in Boston, and colleagues analyzed tumor samples provided by the University of Pittsburgh from 92 patients with head and neck squamous cell carcinoma (HNSCC). The samples were chosen to be reflective of the normal distribution of patients with these cancers, that is, “mostly men and mostly smokers,” noted Tward. Of these patients, 89% reported a history of tobacco use and 79% alcohol use; 14% of all tumors and 53% of oropharyngeal tumors were found to be positive for human papillomavirus.

Tumor sites also were selected so as to be roughly representative of the general HNSCC patient population; thus, most were oral cavity cancers, followed by a substantial proportion of oropharynx cancer samples, and a few from patients with hypopharyngeal or laryngeal tumors, Tward explained.

Investigators used hybrid capture sequencing to compare tumor tissue with nontumor tissue from the same individual. They also compared the total number of mutations in the HNSCC samples with samples from previous tumor studies done at Broad. Tward noted that HNSCC clusters with lung cancer, in that both possess a relatively high number of mutations, sometimes referred to as “the smoking cluster.”

The analysis yielded a very large number of mutations; for example, 5000 genes had at least one mutation, and 1300 had at least two. Tward emphasized, however, that most of these are not implicated either in promoting or maintaining the cancer. “The vast majority,” he said, “are what we call ‘passengers,’ that is, mutations alongside another mutation that is acting as a ‘driver.’” Tward said his colleagues at Broad have developed a set of algorithms to help researchers distinguish between the two.

Analysis using these algorithms confirmed earlier findings implicating 

 in head and neck malignancies. Of particular interest, however, are mutations they discovered that have not previously been implicated in these cancers: 

Tward explained that NOTCH, depending on the cell in which it resides, can act either as an oncogene (as is the case with acute lymphoblastic leukemia) or as a tumor suppressor gene in HNSCC and skin cancer; in these cancers, NOTCH is “a critical player in the decision to stop proliferating,” he continued. When mutations inactivate NOTCH, terminal differentiation ceases, causing unrestrained proliferation. To illustrate the challenge posed by NOTCH’s dual mechanisms, Tward noted a clinical trial testing a gamma secretase inhibitor predicted to inhibit NOTCH in patients with Alzheimer’s disease that had to be stopped because the drug was causing an increase in squamous cell cancers in the treatment arm.

The researchers also found that mutations in genes at the “top of our rank list” for head and neck cancers and defects in squamous differentiation also are present in patients with cleft palate syndromes. “We think this is all related,” said Tward.

“When we add all this up, we come up with wiring patterns in head and neck cancer,” which can be used to inform further studies. He added that researchers did not find many oncogenes in these tumor samples, an exception being 

. Tward suggested that trials with PI3K inhibitors are likely to be fruitful in patients with HNSCC, but “only for those who have the mutation.” He also noted that investigators did not find 

 mutations, a finding consistent with the much larger Cancer Genome Atlas (TCGA) data set.

	Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. 

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Scientists now know a lot more about the genetic landscape of head and neck cancer and hope that eventually this knowledge will lead the way to new therapies.

Searching for New Pathways and Treatments for Head and Neck Squamous Cell Carcinoma

Circulating tumor cell (CTC) counts can provide a variety of useful information for clinicians treating patients with metastatic breast cancer (MBC), according to Massimo Cristofanilli, MD, professor of Medicine and the G. Morris Dorrance Jr Endowed Chair in Medical Oncology at the Fox Chase Cancer Center in Philadelphia, Pennsylvania. At the 2012 Chemotherapy Foundation Symposium, Cristofanilli highlighted research that he believes supports the use of CTC testing in MBC management.

CTCs are tumor cells that have detached from solid tumors and entered the patient’s peripheral blood. In patients with MBC, studies have shown that the number of CTCs found in the peripheral blood before and during treatment is a predictor of progression-free survival (PFS) and overall survival (OS). CellSearch, which is manufactured by Veridex, LLC, is the only FDAapproved diagnostic test for CTC enumeration in metastatic disease.

Cristofanilli first discussed a 2004 study showing MBC patients with <5 CTCs/7.5 mL of peripheral blood experienced longer PFS than those with counts ≥5 mL—21.9 months and 10.9 months, respectively (

. 2005;23[suppl; 524]). He next described findings from a pool analysis of six studies involving a total of 841 patients with progressive MBC 

 2011;29[suppl; abstr 10592]) that indicated that baseline levels of CTCs are the “best predictor of overall survival.”

CTCs also have demonstrated strong prognostic value for patients receiving endocrine therapy or chemotherapy alone; however, in patients receiving bevacizumab or HER2-targeted therapy, Cristofanilli noted, baseline CTCs did not predict OS (

In evaluating the role of CTCs in site of recurrence, Cristofanilli said investigators looked first to see if CTCs would help in evaluation of bone metastases, and they found that bone metastases alone and in combination with other sites, “were discriminated according to more or less than 5 CTCs.” Patients with either bone-only metastases or visceral metastases with CTC counts ≥5 did worse than those with CTCs <5 (

Cristofanilli also discussed the role of CTCs in measuring progression, where enumeration has proven beneficial as a complement to imaging (

 2006;12[21]:6403-6409). Researchers have looked into the question of whether patients with >5 CTCs will progress faster, and found it to be “a very good determination of progression,” he said, particularly in visceral metastases.

Presenting new data on studies of patients (N = 146) with oligometastatic disease, Cristofanilli noted that typically these patients do better in terms of OS, but patients with >5 CTCs do worse. Researchers found a statistically significant difference in time to new metastatic sites for oligometastatic patients with >5 CTCs. Median survival was 40.2 months for patients with <5 CTCs versus 15.8 months for those with ≥5 CTCs. Time to new metastatic lesions also revealed a clear difference in median survival based on CTC counts in oligometastatic patients: 17.7 months for patients with <5 CTCs and 7.2 months for those with ≥5 CTCs. Thus, “with a standard test of CTCs, you can predict and follow very clearly the progression of disease,” Cristofanilli said.

Molecular monitoring is another area where CTC enumeration can play an important role, and the next step, said Cristofanilli, is to better understand the tumor markers expressed in CTCs. The CellSearch technology can enumerate and characterize CTCs for tumor markers that predict endocrine sensitivity (ER and Bcl-2) and resistance (HER2 and Ki67). A phase II trial (COMET-1) is in development to determine a CTC-endocrine therapy index (CTC-ETI) in ER-positive, HER2-negative MBC patients that can be used before a new endocrine therapy is initiated to identify patients likely to progress rapidly.

Circulating tumor cell counts can provide a variety of useful information for clinicians treating patients with metastatic breast cancer.

Should Analysis of Circulating Tumor Cells Be Part of Metastatic Breast Cancer Management?

A retrospective study of older women with early-stage breast cancer who received adjuvant trastuzumab alone or in combination with anthracyclines has revealed a higher incidence of heart failure (HF) and cardiomyopathy (CM) in these patients compared with older breast cancer patients who had no adjuvant therapy. The findings were published online in the Journal of the American College of Cardiology.

Cardiotoxicity is a particular concern for patients with breast cancer undergoing adjuvant therapy, because many commonly used drugs can cause left ventricular function abnormalities. Over 40% of women diagnosed with breast cancer in the United States are at least 65 years of age, yet the elderly have been underrepresented in trastuzumab clinical trials.

For the study, Jersey Chen, MD, MPH, assistant professor of Medicine at the Yale School of Medicine, New Haven, Connecticut, and colleagues used data from the National Cancer Institute’s SEER-Medicare database from 2000-2007 to identify 45,537 women aged 67 to 94 years (mean, 76.2 years) with early-stage breast cancer.

Because most patients treated with trastuzumab were treated from 2005 onward, investigators looked at cumulative incidence of HF or CM up to 3 years after breast cancer diagnosis. Incidence rates for HF or CM were calculated among five patient groups divided according to treatment approach: trastuzumab (with or without nonanthracycline chemotherapy); anthracycline plus trastuzumab (A+T); anthracycline (without trastuzumab and with or without nonanthracycline chemotherapy); other nonanthracycline chemotherapy; or no adjuvant chemotherapy or trastuzumab therapy.

One percent of the cohort received trastuzumab (n = 431); 0.9% received A+T (n = 437); 11.5% received anthracycline-based chemotherapy (n = 5257); 5.9% received nonanthracycline chemotherapy (n = 2712); and 36,700 (80.6%) received neither adjuvant chemotherapy nor trastuzumab.

Medicare claims data were used to determine cardiac events. At 3 years postdiagnosis, cumulative incidence of HF or CM was significantly higher (P <.001) for patients receiving trastuzumab (26.7 per 100 patients) and A+T (28.2 per 100 patients), compared with patients who received no adjuvant therapy (16.9 per 100 patients). Patients who received anthracyclines were less likely to have HF or CM compared with patients who received no adjuvant therapy (15.3 vs 16.9 per 100; P <.0001). The 3-year HF or CM incidence for patients who received other types of chemotherapy was not significantly different from patients who received no adjuvant therapy (17.0 vs. 16.9 per 100 patients; P = .89).

When adjusted for potential confounders, such as age, race, and marital status; breast cancer characteristics; cardiovascular conditions; and year of breast cancer diagnosis, the researchers reported adjusted 3-year incidence rates per 100 patients of 32.1 in the trastuzumab-only group; 41.9 in the A+T group; 20.2 in the anthracycline group; 19.2 for patients receiving nonanthracycline chemotherapy; and 18.1 in patients receiving no adjuvant therapy.

“Intrinsic differences in the mechanisms of cardiotoxicity may be one explanation for why the risk of developing HF or CM was higher with trastuzumab than with anthracycline therapy,” the researchers wrote, adding that another possible explanation for the difference could be that clinicians selected lowest-risk patients for anthracycline therapy due to its cardiotoxicity profile.

	Chen J, Long JB, Hurria A, et al. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer [published online ahead of print November 2, 2012]. 

A retrospective study of older women with early-stage breast cancer who received adjuvant trastuzumab alone or in combination with anthracyclines has revealed a higher incidence of heart failure and cardiomyopathy.

Cardiac Risks Higher in Older Women Receiving Adjuvant Trastuzumab

If there were just one takeaway about prostate cancer navigation that Frank delaRama, RN, MS, AOCNS®, would like his peers attending NCONN 2012 to remember, it would be the important role they have in helping patients make informed decisions about their treatment.

A strong advocate for empowering patients through a shared decision-making (SDM) model, delaRama, clinical nurse specialist with the Cancer Care Centers, Palo Alto Medical Foundation, noted that prostate cancer is different from other cancers in many respects, and that in its early stages, physicians are not always able to determine how the cancer will act. Information is key, as patients with early-stage prostate cancer typically choose among three standard treatment options: watchful waiting/active surveillance, surgery, and radiation—the latter two options carrying the risk of both physical and psychosocial side effects.

For later-stage patients, “again, it’s all about information and education, whatever the stage is,” delaRama stressed. Logistics remain important supports that the oncology nurse navigator (ONN) can provide—for example, making sure patients get to their appointments, setting up a timeline for scheduling them, and assisting with transportation needs&mdash;but he also sees a vital role for ONNs in arming patients with information, resources, and decisionmaking tools that will help them in choosing the best options for their own treatment (

Frank delaRama on Patient Education in Prostate Cancer

He suggests patients use an SDM process to make their treatment choices, starting with having all relevant clinical information on their cancer, knowing the treatment options, and then prioritizing goals and outcomes, such as removing the cancer, avoiding long-term side effects, maintaining quality of life, convenience, and cost. “We are not giving medical advice, but rather giving patients tools to come to an informed decision—a decision that they will own,” said delaRama.

“In prostate cancer, the ONN provides a unique, valuable service as an SDM coach. Patients who use SDM are more satisfied with their treatment decisions, regardless of outcomes,” he concluded.

Information is key, as patients with early-stage prostate cancer typically choose among three standard treatment options: watchful waiting/active surveillance, surgery, and radiation.

Helping Prostate Cancer Patients to Make Informed Treatment Decisions

For Johns Hopkins’ gastrointestinal cancer surgeon Mark D. Duncan, those who help his patients cope with their diagnosis and manage their often complex treatment and follow-up are critical members of the healthcare team–whether they are nurse practitioners, oncology nurses/navigators, or, as in his case, a physician’s assistant. In fact, he would like to see more GI nurse navigators for a specialty where currently there are not enough.

Gastric cancers represent the second-leading cause of cancer deaths worldwide, noted Duncan, MD, FACS, during a presentation at the 4th Annual National Coalition of Oncology Nurse Navigators Changing the Face of Cancer Care Conference, October 4-6 in Nashville, Tennessee. Regardless of the tumor type, “surgery is front and center in these cancers,” and is frequently followed by some complication. At least initially, “all of my patients will lose weight,” and we have to ask ourselves, “If they don’t start to gain weight, is that the effects of surgery, or do they still have cancer?”

“With the tumors I treat, I don’t save most patients, but I treat all,” Duncan said. In getting them back on their feet, “a lot depends on the patient.” His patients tend to be older, with comorbidities to consider. Patients usually come to him with weight loss and malnutrition; fatigue is also an important factor, whether it stems from the effects of aging, the disease itself, or pretreatment of the tumor with radiation or chemotherapy. Radical GI cancer surgery can mean lifelong changes in body function and quality of life–making the patient’s overall fitness, as well as family support, crucial.

Duncan described several of his own surgical cases to illustrate the wide range of issues clinicians confront when treating cancer patients. One typical older patient had to overcome her general distrust of physicians, simultaneously deal with her husband’s illness, and manage the basic logistics of getting to treatment and knowing whom to call with questions. One younger patient raised understandable questions about fertility and sexual activity. A single parent wondered how she could take time off from her job, what to do about her children with her extended family living out of state, and whether to believe what she learned in an Internet chat room versus what her oncologist told her. Other patients must confront language and cultural barriers or cost issues, which can mean missed appointments and difficulties in understanding their diagnosis, treatment, and follow-up care.

“The navigator is the glue that holds this all together,” said Duncan, “the secret weapon,” which he said is deployed most effectively in the areas of communication and coordination. This means communicating with patients and doctors, providing resources and guidance, and empowering patients to help set goals for themselves and make treatment decisions. It also means centering care on both patients and their families. “Cancer is personal. It doesn’t just affect patients, it affects people with families,” Duncan said.

While noting “a paucity of hard data” on navigation’s benefits, he cited several recently reported positive outcomes studies, including one by researchers at the Edinburgh Cancer Centre in Scotland (

. 2012;21[9]:986-992) who found that navigated patients with prostate cancer were more confident in making treatment decisions, more certain they had made the right decision after consultation, and had fewer regrets about their decision six months later.

Patients’ Guide to Cancer of the Stomach and Esophagus

When the Connecticut Veterans Affairs HealthcareSystem hired an advanced practice nurseto serve as a cancer care navigator, researchers reported a reduction in the average time from suspicion of cancer to treatment for patients with non-small cell lung cancer (NSCLC) from 136 days in 2003 (before the new position was established) to 55 days in 2010, as well as a trend toward diagnosis of NSCLC at an earlier stage (

. 2012;16[1]:29-36). In another study, researchers at the University of Southern California found that oncology nurse navigation proved to be an effective outreach strategy for increasing participation of black patients in cancer research, and may be achieved at nearly half the cost of traditional methods of enrolling patients in clinical trials at cancer centers (

Duncan said that he would like to see more attention, funding, and advocacy for GI cancers. Such attention might yield more cancer navigators for the specialty. He believes more navigation also would help increase participation in clinical trials among those traditionally underrepresented, and meet the real need of all patients to better understand these cancers and manage their treatments and follow-up care. Toward that end, he has authored a book, 

, as part of The Johns Hopkins Patients’ Guide series. 

For Johns Hopkins' gastrointestinal cancer surgeon Mark D. Duncan, those who help his patients cope with their diagnosis and manage their often complex treatment and follow-up are critical members of the healthcare team.

Surgeon Offers Perspective on Need for GI Navigators

Not surprisingly, melanoma nurse practitioner Rajni Kannan is passionate about helping her patients at NYU’s Cancer Institute to fight this devastating disease.

That’s why Kannan, BS, MS, RN, ANP-BC, is excited about the remarkable developments she’s seen in the treatment of metastatic melanoma over the last 5 years—including last year’s FDA approval of two new agents, ipilimumab and vemurafenib.

At the same time, Kannan is determined to reduce the number of patients she sees at the Manhattan facility based at the Langone Medical Center by being an advocate for increased awareness of the dangers of tanning, she told attendees during a presentation at NCONN 2012.

The incidence of melanoma, the deadliest of all skin cancers, is quickly rising, and the disease is responsible for more than 8000 deaths each year, Kannan said, adding that the average survival for melanoma patients with metastatic disease is 7 months, and that 50% of these patients will develop brain metastases. Kannan reminded audience members that exposure to ultraviolet (UV) radiation is a major risk factor for skin cancer, and that the World Health Organization has declared UV-emitting tanning devices carcinogenic.

In discussing ipilimumab (Yervoy), Kannan described the mechanism of the immunotherapy as “amazing.” The treatment is given intravenously every 3 weeks for a total of four doses, and Kannan explained that “patients have had a hard time understanding that they get four doses, and that’s all they get” before returning for tumor evaluations after 12 and 24 weeks and then every 3 months thereafter. Kannan noted that nurses have an important role to play in explaining to worried patients that “this is enough.”

The other new agent, vemurafenib (Zelboraf), is a targeted therapy approved for patients with unresectable or metastatic melanoma who test positive for the 

mutation—approximately 40% of melanoma patients, according to Kannan. Testing for 

 mutational status, she said, must be conducted at a site of metastatic disease, presenting another important role for oncology nurses and navigators: to help patients with earlier-stage cancers understand why they can’t be tested. Moreover, she said, “if you give this drug to patients who don’t have the mutation, you can actually accelerate the disease.”

“Eighty percent of patients respond to vemurafenib, but the question is, for how long?” Kannan noted. In some patients, disease quickly returns, while others do extremely well. “We need to determine why some patients have a sustained response,” she said.

These two agents offer new hope for metastatic melanoma patients, but both have complex side-effect profiles. Nurses are important in this regard, too, Kannan said, since they can share their expertise about the drugs with patients, who often “don’t communicate well about their side effects.”

National Comprehensive Cancer Center guidelines recommend clinical trials as first-line therapy for metastatic melanoma patients, and a number of new agents are under investigation for treatment of the disease, Kannan reported. PD-1, an immune checkpoint inhibitor, is about to go into phase III testing. Researchers are also looking at MEK inhibitors, vaccines, and combination therapies.

This is an area where nurse navigators also can make a huge difference, she said, by helping patients locate not only the right trials for their diseases, but also studies that will accept their health insurance plans. Kannan stays abreast of virtually all relevant clinical trials underway at NYU and elsewhere. “It’s not about us,” she said. “We’ll send patients anywhere to get the care they need.”

Kannan is currently writing a grant application to establish a melanoma survivorship program at NYU. “Survivorship is now a reality in melanoma,” she said, “but we don’t have the magic medicine yet.”

The incidence of melanoma, the deadliest of all skin cancers, is quickly rising, and the disease is responsible for more than 8000 deaths each year.

New Metastatic Melanoma Therapies Create Hope for Patients, Key Role for Oncology Nurses

One recent development on the minds of NCONN 2012 attendees is the new patient navigation standard announced in March by the American College of Surgeons Commission on Cancer (CoC). Facilities seeking CoC accreditation now need to have a patient navigation process in place by 2015.

Mary Lou Woodford, RN, BSN, MBA, CCM, care coordination program director for the Massachusetts Department of Health, offered practical guidance to the group on how to use the CoC standard to help their institutions design programs that break down barriers and ensure equal access to care in the communities they serve.

	“My Hospital Is CoC-Accredited: What Do I Need to Do to Comply?”

When Woodford hears this question, and she often does, she explains that under 

, facilities will need to demonstrate that they have a process in place that removes barriers to care. This does not mean that facilities have to employ patient navigators; however, Woodford emphasized these key elements:

		Perform a community “needs assessment” to documents disparities and barriers to care for patients in the community

		Identify resources—either on-site or through referral&mdash;to address these disparities / barriers

		Present patient navigation process to cancer committee annually for formal evaluation

		Modify or enhance patient navigation process to address results and recommendations from the committee evaluation

“To do a thorough needs assessment, and to do it well, can take 12 months,” noted Woodford. “Look at your own state’s comprehensive cancer plan. Every state health department has one. They can help you get the data you need for the assessment.”

She emphasizes that CoC is looking for measurable data on what prevents some people from accessing care at a facility and cites community interviews and focus groups as examples of ways to secure the required data. “Bringing in other units, such as cardiovascular or chronic disease specialists, to work with you on the needs assessment may also be an approach that will work for your facility,” Woodford added.

The purpose of the assessment, Woodford explained, is to identify: (1) the needs of the population a facility serves, (2) health disparities in the community, and (3) resources to prevent barriers and improve access to care. Armed with this information, facilities can create building blocks for program development, implementation, and evaluation.

“The assessment is broader than just who comes to your facility,” said Woodford.  “You need to get into the community and find out why some people don’t access care.”

Woodford pointed out that it would be hard for one individual, such as a navigator, to set up this process alone, and suggested engaging a multidisciplinary group at each facility to work on the project. Members of the multidisciplinary team  might include evaluation research, quality improvement, discharge planning, medical records, and community resources.

Despite the extended 2015 deadline, Woodford strongly advised facilities to get started no matter where they happen to be in their own CoC 3-year survey cycle for accreditation. “[The CoC] wants facilities to succeed. If you start working on implementation before the survey staff visit, it will be a great opportunity to get their guidance. We all know what the standard is, and survey evaluators will be looking at your progress.”

“The ultimate goal is to serve the whole community,” concluded Woodford.

For more information on the standards, visit 

Facilities seeking Commission on Cancer accreditation now need to have a patient navigation process in place by 2015.


Lauren M. Green