 The authors of a case study presented at the 21st Annual Congress of the American Association of Clinical Endocrinologists noted that multiple endocrine neoplasia (MEN) type 2 is “a syndrome of familial cancers with autosomal dominant inheritance basically characterized by Medullary Thyroid Cancer (MTC).” The MEN 2A subtype, which makes up around 90% of cases of MEN, is caused by mutations in the 

 protooncogene, most commonly resulting in “the substitution of one of six cysteine residues in exon 10 and 11;” MEN 2A is “most frequently caused by activating mutations of the extracellular codon 34.”

Patients with MEN 2A often develop cutaneous lichen amyloidosis, primary hyperparathyroidism (about 15-30% of cases), pheochromocytoma (about 50%), and MTC (about 95%). MEN 2A may be indicated when patients develop bilateral or multifocal MTC, or when MTC presents at an early age (younger than 3-5 years). Diagnosis relies on clinical findings, family history, and genetic testing of the 

In “Multiple Endocrine Neoplasia Type 2A: Study of a Family of Three Generations with Pedigree Analysis of the RET Protooncogene,” Galesanu and colleagues reported on the results of genetic screening of the 

 protooncogene for mutation exons 10 and 11, codons 609, 611, 618, 629, 630, and 634, in three generations of a family in which the first patient (proband) presented with “bilateral pheochromocytoma associated with MTC.”

Out of nine family members screened, six (proband, three daughters, and two male grandchildren) were found to have the 

 protooncogene mutation codon 634 (Cys 634 Trp) in exon 11. The proband and one daughter had bilateral pheochromocytoma and MTC, two daughters had unilateral pheochromocytoma (one with confirmed MTC, one with nodular goiter and increased serum calcitonin), and one of the male grandchildren also has increased serum calcitonin.

The authors noted that risk-reducing thyroidectomy is a preventive option for all subtypes of MEN, and is recommended in many cases by the American Thyroid Association. The case findings presented here confirm that “genetic screening for germline 

 protooncogene mutation in hereditary medullary thyroid cancer is accurate,” enabling patients who are carriers of the mutation to opt for early prophylactic surgery. However, this can be a difficult decision for parents of young children to make—in this case study, although the two grandchildren carry the 

 mutation, their parents opted against total thyroidectomy, underscoring the need for further study of “the psychosocial impact of genetic testing for MEN 2” and the challenges of accepting surgical treatment and lifelong follow-up surveillance.

Articles

Results of a multi-generational case study strengthen the case for genetic screening in cases of hereditary thyroid cancer.

Carriers of Mutation Responsible for Multiple Endocrine Neoplasia Can Face Difficult Choices

Study results presented by Guerrero and colleagues at the 21st Annual Congress of the American Association of Clinical Endocrinologists showed that where a patient lives when he or she is diagnosed with thyroid cancer can have an effect on the stage at which the cancer is diagnosed and on cancer-free survival (CFS) rates.

Using information from the Surveillance Epidemiology and End Results (SEER) database, the authors identified more than 87,000 individuals diagnosed with thyroid cancer between 1973 and 2008, assessing for historical stage of diagnosis and CFS according to geographic region. The data were stratified by thyroid cancer type, race/ethnicity of the patient, age, year of diagnosis, and registry site. Data were excluded for Hawaii and Alaska natives, patients with cancer stage 0 or unknown stage at diagnosis, patients who had been previously diagnosed with tumors, patients whose age was unknown at diagnosis, and patients for whom survival information was missing.

The four geographic regions for this study were: West (including data from San Francisco-Oakland, New Mexico, Seattle, Utah, San Jose, Los Angeles, and other locales), South (Atlanta and rural Georgia, Kentucky, and Louisiana), East (Connecticut and New Jersey), and Midwest (Detroit and Iowa). Fifty-five percent of individuals analyzed were from the West, 12% were from the South, 18% were from the East, and 15% were from the Midwest.

The authors reported that 60% of patients presented with localized disease, 34% with regional metastasis, and 5.6% with distant metastasis. Papillary thyroid cancer was the most prevalent diagnosis across regions and ethnicities (West: 85%, South: 82%, East: 83%, Midwest: 79%), followed by follicular thyroid cancer (West: 7.3%, South: 9%, East: 7.7%, Midwest: 10.7%). Median age at diagnosis was consistent across regions (roughly 46-48 years of age).

Regional differences in thyroid cancer stage and survival included:

		Patients in the West region had a higher risk of presenting with regional and distant metastases

		Patients in the East with follicular cancer were more likely to have local disease 

The large majority of patients in this study were female (at least 75% of the patient population in each region) and non-Hispanic white (66-87% of the population in each region, with the highest concentration in the South and Midwest). The authors reported “no significant difference in CFS by geographic region for non-Hispanic white or Hispanic white individuals,” but did find that “blacks from the West had significantly better CFS than blacks from the South.”

The authors concluded that “there are differences in the stage of presentation and survival of individuals with thyroid cancer according to geographic region.” They identified socioeconomic factors, access to healthcare, and cultural beliefs as potential contributing factors.

The data in this study were also used to determine “if there were any differences in treatment before and after the publication of the 2006 American Thyroid Association management guidelines for thyroid nodules and thyroid cancer.” The authors determined that “more patients received a sub-total, near-total, or total thyroidectomy, and more patients had lymph node dissections” after publication of the guidelines. They reported that “stage of presentation and use of radioactive iodine ablation did not change” after the guidelines were published.

Patients are more likely to present with regional or distant metastases and experience lower rates of cancer-free survival depending on where they live.

Researchers Find Regional Differences in Stage of Presentation and Survival of Individuals With Thyroid Cancer

According to study results presented at the 21st Annual Congress of the American Association of Clinical Endocrinologists, overexpression of pituitary tumor transforming gene 1 (

) is associated with low survival rates in patients with adrenocortical carcinoma (ACC). However, treatment with vorinostat, which decreases 

 expression, may be suitable for targeted treatment of ACC.

Researchers extracted RNA from 100 mg samples from 19 flash-frozen ACC tumors, along with RNA from four normal adrenal glands. Sixty-three percent of the patients from whom the tumors were extracted were female, with an average age of 47.6 years. Median survival was 5.9 years. The average tumor size was 9.7 cm and 351 g.

Using gene expression profiling, the authors examined the samples and “identified marked dysregulation of the cell cycle control, focused on sister chromatid adhesion and cytokinesis in the G2/M transition.” In particular, they reported potential alterations in activity of the tumor suppressor gene 

, noting that “genes that are normally repressed by 

 were overexpressed, and those that are normally promoted had decreased expression.”

The researchers identified overexpression of 

, which encodes the antibody securin, “a negative regulator of 

 and a protein involved in the G2/M transition,” as a marker of poor survival. Patients with tumors expressing high levels of 

 levels had a median survival of 1.2 years, whereas patients with tumors expressing lower levels of 

Treating two ACC cell lines (SW-13 and H295R) with the histone deacytlase inhibitor vorinostat “decreased securin levels in both cell lines and inhibited cell growth with IC50 values of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively.”

This may be a potentially promising development because, as the authors noted, ACC “is an aggressive malignancy with poor overall five-year survival (16-22%).” Complete surgical excision is the only current treatment with the potential to cure ACC. However, up to 70% of patients have metastases at the time of diagnosis, ruling out surgery. Current chemotherapy options are limited for ACC—the antineoplastic drug mitotane has only a 25% response rate. In the recently concluded FIRM-ACT study, patients with ACC treated with a regimen of etoposide, doxorubicin, cisplatin, and mitotane had a median overall survival of 14.8 months. The response rate for this regimen was only 24%.

The authors noted that limited options currently available to patients with ACC underscore the “continued need to understand the underlying molecular pathogenesis of ACC and develop new therapies.” Further study of the effect of overexpression of 

 on survival in ACC and the potential of vorinostat to inhibit cell growth is warranted.

Researchers find that overexpression of a specific gene is associated with poor survival in patients with adrenocortical carcinoma.

Genetic Data Points to Potential New Therapeutic Target for Adrenocortical Carcinoma

Archimedes Pharma, Ltd, announced recently that it had received FDA approval for Lazanda (fentanyl) nasal spray for the management of breakthrough pain in adult cancer patients. The drug was approved for patients who are either already receiving or are tolerant to opioid therapy for persistent cancer pain.

Lazanda is the first fentanyl nasal spray approved in the United States. In a news release announcing the approval, Donald Taylor, MD, director at Taylor Research LLC, said Lazanda provides a new approach to managing the “inadequately treated episodes of breakthrough pain that many patients with cancer experience.” Lazanda is expected to be available later this year and will include a Risk Evaluation and Mitigation Strategy (REMS) that will require pharmacies, distributors, and healthcare professionals to enroll in the REMS program to dispense, distribute, and prescribe the drug.

The FDA approval comes in the wake of the publication of several studies in clinical journals demonstrating the effectiveness and tolerability of fentanyl nasal spray in patients suffering from episodes of breakthrough cancer pain. One study, published in the June 2011 issue of 

, reported that in 2 randomized, double-blind, crossover trials in opioid-tolerant adults, fentanyl pectin nasal spray (delivered in 100—800&thinsp;μg titrated doses) was “significantly more effective than placebo in reducing pain intensity and provided a significantly faster onset of pain relief than oral immediate-release morphine.”

, another study compared fentanyl pectin nasal spray to immediate-release morphine sulfate in the treatment of breakthrough cancer pain. The trial enrolled 110 patients who were being treated with ≥60 mg per day of oral morphine for persistent cancer-related pain and who experienced up to 4 breakthrough cancer pain episodes per day. Patients were then randomized to receive either fentanyl pectin nasal spray plus placebo or immediate-release morphine sulfate plus placebo for 5 breakthrough cancer pain episodes each. Researchers assessed pain intensity, pain relief, patient acceptability scores, and adverse events, and found that fentanyl pectin nasal spray “consistently provided relief from pain more rapidly” than immediate-release morphine sulfate. More than 75% of patients in the trial reported being “satisfied” or very satisfied” with the convenience and ease of use of fentanyl pectin nasal spray.

In a final study, investigators evaluated the safety and tolerability of fentanyl pectin nasal spray in more than 400 patients with cancer. Eligible patients were being treated with morphine for background pain and experiencing up to 4 episodes of breakthrough cancer pain each day. The results, published in the March 2011 issue of 

found that nearly one-quarter (24.6%) of patients in the study reported generally mild/moderate treatment-related adverse events that are typical of opioids. The study also revealed that 94% of breakthrough cancer episodes treated with fentanyl nasal spray required no additional use of rescue medication, and that more than 90% of patients did not have to increase doses during the study.

Lazanda uses the PecSys drug delivery system, which delivers fentanyl rapidly in a fine mist that gels to mucosal surfaces, thereby optimizing the absorption of lipophilic drugs into the blood stream. The manufacturer, Archimedes Pharma, is an international specialty pharmaceutical company that has offices throughout the United States and Europe.

	Lyseng-Williamson KA. Fentanyl pectin nasal spray: in breakthrough pain in opioid-tolerant adults with cancer. 

	Davies A, Sitte T, Elsner F, Reale C, Espinosa J, Brooks D, Fallon M. Consistency of efficacy, patient acceptability, and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulfate in breakthrough cancer pain

	Radbruch L, Torres LM, Ellershaw JE, et al. Long-term tolerability, efficacy and acceptability of fentanyl pectin nasal spray for breakthrough cancer pain. 

. 2011 Mar 22. [Epub ahead of print]. doi:10.1007/s00520-011-1124-x.

FDA approvad Lazanda (fentanyl) nasal spray for the management of breakthrough pain in adult cancer patients.

Todd Kunkler

Articles

Carriers of Mutation Responsible for Multiple Endocrine Neoplasia Can Face Difficult Choices

Researchers Find Regional Differences in Stage of Presentation and Survival of Individuals With Thyroid Cancer

Genetic Data Points to Potential New Therapeutic Target for Adrenocortical Carcinoma

FDA Approves First Fentanyl Nasal Spray for Breakthrough Cancer Pain