	CYP2D6 phenotype status does not predict tamoxifen efficacy in patients with early-stage breast cancer, according to a retrospective analysis of data from the Breast International Group (BIG) 1-98 trial

 presented at SABCS. Freya R. Schnabel, MD, professor of surgery, NYU School of Medicine, discussed the findings at the JTCC’s SABCS review. Based on the negative results, Schnabel believes there is no current justification for CYP2D6 pharmacogenetic testing prior to administering tamoxifen.

	CYP2D6 is involved in the formation of endoxifen, a metabolite linked to tamoxifen’s efficacy. Previous research, including Schroth et al

, had suggested an association between lower CYP2D6 activity and worse clinical outcomes with tamoxifen treatment. Schnabel admitted the data had been convincing. “I was very sold on the idea that CYP2D6 profiling would be important in the consideration of women who were going to take tamoxifen for chemoprevention,” she told conference attendees. However, subsequent research, including the BIG 1-98 retrospective analysis, altered Schnabel’s opinion.

	The BIG 1-98 trial examined tamoxifen and letrozole

 administered alone and sequentially as adjuvant treatment in 8010 postmenopausal women with early-stage, endocrine-responsive breast cancer. At SABCS, Brian Leyland-Jones, MD, PhD, professor of medicine at Emory University, in Atlanta, presented data from a subanalysis of 2675 BIG 1-98 patients who had received monotherapy with either tamoxifen or letrozole.

 The patients were genotyped for CYP2D6 and categorized as poor, intermediate, or extensive metabolizers. The primary endpoint was breast cancer—free survival.

	The researchers discovered no association between CYP2D6 status and breast cancer—free survival. Defying expectations, clinical outcomes were not worse in poor and intermediate metabolizers than in extensive metabolizers. Previous chemotherapy treatment was also not a factor. The results suggest CYP2D6 genotyping will provide no indication of tamoxifen’s potential effectiveness.

	The study also investigated whether CYP2D6 phenotypes associated with reduced enzyme activity produced fewer hot flashes, a common side effect of tamoxifen. It has been theorized that lower enzyme activity would reduce tamoxifen’s activity, and thus lower the incidence of its side effects, including hot flashes. However, the BIG 1-98 subanalysis results showed no association between hot flash occurrence and metabolizer status. Hot flashes occurred in poor, intermediate, and extensive metabolizers at rates of 48%, 49%, and 42%, respectively. Based on these statistically insignificant differences, the study concluded that hot flash incidence should not be a marker of tamoxifen efficacy.

	The negative results of Leyland- Jones et al’s study, along with the similar outcome of Rae et al’s

 retrospective analyses presented at SABCS, have established a convincing argument against CYP2D6 genotyping prior to tamoxifen administration. The CYP2D6 controversy will likely continue, however, until the completion of prospective analyses such as the Eastern Cooperative Oncology Group’s ongoing E3108 study (

	For her part, Schnabel has doubts that the prospective trials will shift the pendulum back toward testing. “Prospective trials are critical, but the data presented by Dr Rae and Dr Leyland- Jones were compelling. I will await the results of these trials with interest, but I am now a bit skeptical, and the proof will have to be very strong to influence practice in favor of testing.”

		Leyland-Jones B, Regan MM, Bouzk M, et al. Outcome according to CYP2D6 genotype among postmenopausal women with endocrineresponsive early invasive breast cancer randomized in the BIG 1-98 trial. Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 9-12, 2010; San Antonio, TX.

		Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302(13):1429-1436.

		Rae JM, Drury S, Hayes DF, et al. Lack of correlation between gene variants in tamoxifen metabolizing enzymes with primary endpoints in the ATAC trial. Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 9-12, 2010; San Antonio, TX.

Articles

CYP2D6 phenotype status does not predict tamoxifen efficacy in patients with early-stage breast cancer, according to a retrospective analysis of data from the Breast International Group

The Final Word on CYP2D6 Testing and Tamoxifen?

The National Cancer Institute (NCI) estimates that sexual dysfunction rates among cancer survivors range anywhere between 40% and 100%. Survivors of both sexes often experience a loss of desire and the inability to reach orgasm. Females also report dyspareunia (pain with intercourse) and a loss or change in genital sensation, while men suffer from erectile dysfunction, anejaculation (absence of ejaculation), and retrograde ejaculation (ejaculation going backward into the bladder).

	Sexual dysfunction stems from both physiological and psychological causes, so treatment requires a comprehensive approach. Additionally, sexual problems often last much longer than other side effects of cancer treatment, so sexual health remains an issue well into survivorship.

	Michael Krychman, MD, medical director of Sexual Medicine at Hoag Memorial Presbyterian Hospital, and executive director, Southern California Center for Sexual Health and Survivorship Medicine, discussed sexual dysfunction at the Second Annual National Coalition of Oncology Nurse Navigators (NCONN) Conference in December 2010. Although Krychman’s information pertained to breast cancer, he said his message applied to all patients with cancer.

	The NCI estimates that 50% to 90% of breast cancer survivors have some form of sexual issue. Some of the more upsetting comments Krychman has heard from his patients include, “Yes, I’m thankful to be alive, but I am dead down there,” and “They never told me I would feel like this.” In his presentation, Krychman addressed some of the causes and treatments of sexual dysfunction in breast cancer survivors.

Breast Cancer Treatments and Sexual Health 

	Krychman said that despite treatment advances that preserve more of the breast, surgical intervention still affects sexual functioning. Evidence from several reviews suggests that breast conservation or reconstruction does not greatly impact preservation of sexual function versus mastectomy. “We would assume that those having breast conservation [surgery] do better sexually than those that have a mastectomy, but that is not necessarily the case,” said Krychman. Although those receiving conservative operations are more likely to enjoy breast caressing, the two groups do not differ on issues such as coital frequency, ease of orgasm, and overall sexual satisfaction.

	Side effects of radiation treatment that can cause sexual dysfunction include volume loss, retraction, fatigue, dryness of skin and erythema, loss of normal sensation, discoloration, skin thickening and fi brosis, lymphedema exacerbation, range of motion diffi culties, and alopecia. Krychman also mentioned that some patients and their partners still mistakenly believe the patient becomes radioactive and that intimacy could cause radiation poisoning.

	Krychman listed several side effects of chemotherapy that can disrupt sexual functioning, including premature ovarian failure, amenorrhea, menopausal syndrome, bone marrow suppression, mucus membrane irritation, neurological changes, vaginal muscosal erythrodysesthesia, alopecia (public and private), weight changes, nausea/vomiting, diarrhea/ stomatitis, and fatigue. Chemotherapy can also induce a fl are-up in patients with genital herpes or genital warts.

	According to the NCI’s Website, research suggests the antiestrogen tamoxifen may reduce sexual desire and the ability to reach orgasm. Also, treatment with aromatase inhibitors may cause vaginal dryness and dyspareunia.

	Comprehensive wellness facilities such as Dr Krychman’s Southern California Center for Sexual Health and Survivorship Medicine offer sexual medicine and counseling to cover both physiological and psychological concerns. Patients with cancer often struggle to fi nd an outlet for their sexual issues, and these centers provide access to the proper treatments while maintaining complete discretion.

	Due to the uncertainties and disagreements surrounding hormone therapy, Krychman discussed hormonal treatment for sexual dysfunction within the context of individual risk assessment. Personalized cancer treatment has been the longtime goal in oncology, and Krychman stressed that sexual dysfunction issues require the same approach. Manipulating hormone levels may be too risky in one individual but exactly the right treatment in another.

	Krychman cited data demonstrating that several common therapies are used to treat other medical issues despite presenting their own set of risks. For example, beta-carotene therapy, calcium CHD supplements, and aspirin, can increase the risk of lung cancer, stroke, and GI bleeding, respectively. Likewise, the risk of using a hormonal treatment for sexual dysfunction may be worthwhile for specifi c patients.

	Minimally absorbed local vaginal estrogen products such as Estring (estradiol vaginal ring), Vagifem (a vaginal estradiol tablet), and Premarin Vaginal Cream (an estrogen mixture) raise estrogen levels, which could enhance sexual function and desire in patients with breast cancer, said Krychman. He sited a small, 7-patient study of Vagifem by Kendall et al to suggest treatments can increase estrogen levels. The study concluded Vagifem, at least in the short term, “reverses the estradiol suppression achieved by aromatase inhibitors in women with breast cancer and is contraindicated.”

	Krychman said, “Surgical oncologists, medical oncologists, gynecologists, and patients will often disagree about [the] safety [of estrogen therapy].” When he discussed Kendall et al’s study at ASCO shortly after its release, about half the medical oncologists in the audience strongly objected to any estrogen use.

	Again, Krychman stressed the importance of individual risk assessment. While some women’s estrogen levels may skyrocket, others could experience increased sexual function with manageable estrogen levels. When using estrogen treatment, Krychman recommends implementing a management plan that includes closely monitoring estradiol levels and any abnormal bleeding.

	Although some studies such as Barton and colleagues 2007 research suggest testosterone therapy has no impact on sexual dysfunction, others suggest the treatment may help some patients. The longterm safety effects of testosterone treatment are unknown, so personalized risk assessment, as with all hormonal treatments, is Krychman’s recommended approach. He currently sees 50 mostly late-stage patients with breast cancer who are taking testosterone. Thus far, their hormone levels have remained at acceptable levels.

	Hormones Are Not the ‘Be-All and End-All’

	At the end of his segment on hormone therapies, Krychman concluded, “Women are not ruled sexually by hormones.” He sees women who have no estrogen or testosterone and they have functioning, satisfying sex lives, while others with normal hormone levels experience sexual dysfunction. Sexual issues often stem from emotional or social issues unrelated to hormones, and resolving these issues is the key to treating some patients.

Psychological Issues and Behavior Modification 

	The effects of cancer treatment can greatly damage a woman’s sexual self-esteem—her image of herself as a sexy, desirable woman. The process can also induce depression, anxiety, and stress that reduce the desire for intimacy. Treatment and counseling can help patients manage the psychological issues affecting their sexual health.

	Sexual issues can also arise from simply not making sex a big enough priority. “Often the patient will say, ‘I’m consumed with cancer. I’m consumed with appointments— I’m going from one appointment to the next,’” Krychman said. Reprioritizing and modifying behavior patterns will help patients make time for intimacy.

	Depression and low sexual function often overlap, and Krychman said buproprion (Wellbutrin) may address both symptoms. Buproprion is a norepinephrine and dopamine uptake inhibitor that is not associated with the sexual side effects of other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). In addition to boosting a patient’s mood, buproprion may improve libido. Krychman noted that treating sexual dysfunction with buproprion is an off-label use.

	Complementary therapies such as acupuncture and yoga are often prescribed to individuals with sexual dysfunction. Patients with cancer may fi nd them useful in alleviating the pain, stress, depression, and/or anxiety that is affecting their sexual health.

	Krychman discussed mechanical products (dilators, vibrators) and fl uids that women can use to help rehabilitate their sexual desire and functioning. The self-help tools are highly individualized, both in comfort level and effectiveness. Insurance may cover some of the items. Comprehensive Wellness Centers can help patients obtain these products with maximum discretion, Krychman said.

Journal of the American Medical Association

	Although cancer treatment has come a long way, patient and physician discomfort and misinformation still lead to a suppression of sexual problems. A survey by Marwick published in the 

 (1999;281:2173- 2174) found that while 85% of adults want to discuss sexual functioning with their physician, 71% believe their physician lacks the desire and time to discuss sexual issues, 68% worry they would embarrass their physician, and 76% feel treatments do not exist for their sexual dysfunction.

	Krychman sees a tremendous opportunity for oncology nurse navigators (ONNs) to bridge this communication gap and help patients overcome these obstacles. “As frontline providers, [you] have to start the dialogue because a majority of physicians will not talk about it,” Krychman told NCONN attendees.

	When broaching the topic with patients, ONNs should remain sensitive to the various factors that contribute to a patient’s sexuality, including age, gender, sexual orientation, personal attitudes, and religious and cultural values. Krychman also said ONNs can be direct when initiating the conversation, saying something to the effect of, “It’s important to take care of you as a complete person, I’m going to ask you some questions about sexual function.”

	The bottom line is that sexual health is a major quality of life component in patients with cancer. Through mindfulness, screening, education, and follow-up, ONNs can ensure their patients receive the comprehensive treatment they need.

The National Cancer Institute (NCI) estimates that sexual dysfunction rates among cancer survivors range anywhere between 40% and 100%

Sexual Health & Cancer

	At the the Second Annual National Coalition of Oncology Nurse Navigators (NCONN) Conference in December 2010, Matthew Zachary, musician, brain cancer survivor, and founder of the I’m Too Young For This! Cancer Foundation (i[2]y), energized attendees with his session on empowering young adults with cancer. Zachary discussed the status of the young adult cancer movement and i[2]y’s programs and advocacy efforts.

	The National Cancer Institute (NCI) reports that more than 70,000 adolescents and young adults aged 15-39 years (AYAs) are diagnosed with cancer each year. The cancers most frequently diagnosed in AYAs include lymphoma, leukemia, germ cell tumors (including testicular cancer), melanoma, tumors of the central nervous system, sarcoma, and breast, cervical, liver, thyroid, and colorectal cancers.

	While the War on Cancer has signifi cantly improved survival rates in pediatric and adult patients, the rates for AYAs have essentially remained stagnant since 1975. Cancer research and treatment has focused primarily on the much larger pediatric and adult cancer populations (AYAs makeup <10% of all cancer patients) and AYAs have slipped through the cracks. The NCI has studied the causes and developed potential solutions for AYA cancer disparities. It attributes the lack of progress in AYA cancer rates to

	• Limited access to care and insurance coverage

	• Delayed diagnosis of primary cancers

	• Inadequate treatment practices and settings

	• Poor understanding of the biology and etiology distinguishing the cancers in this population

	• Inadequate collection of patients and patient data

	• Low numbers of clinical trials and poor participation

	• Unique psychosocial and supportive care needs

	• Inconsistent treatment and follow-up care guidelines

	• Limited emphasis on prevention and early detection.

Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer

	To address AYAs’ unique cancer concerns, the NCI collaborated with the Lance Armstrong Foundation on the groundbreaking 2006 report 

. The report, along with a 2007 followup, 

, provided recommendations for improving outcomes in AYAs across the entire cancer care spectrum, including

	• Establish a strong scientifi c foundation to support the biological differences in tumors found in AYAs

	• Leverage completed, ongoing, and new clinical trials to obtain knowledge about cancer in AYAs

	• Increase healthcare provider awareness of AYA issues by working with professional societies and advocacy organizations

	• Facilitate the development of AYA standards for, and availability of, patient navigators and health coaches.

	Zachary faced a much different landscape when he was diagnosed with brain cancer. AYA cancer resources were essentially nonexistent, and the NCI was certainly not focusing on the young adult population.

	In 1995, Zachary was a college senior and concert pianist. He had been accepted to graduate school and his dream of composing music for fi lm was in reach. At the start of the fall semester, however, his left hand began to lose its dexterity and eventually it lost all fi ne motor coordination. When he sought help from the campus medical center, his frustrating experience mirrored that of many AYAs.

	Young adults frequently endure diagnostic delays because of the population’s low incidence rates of cancer. Healthcare professionals will often attribute potential cancer symptoms to fatigue, stress, or other causes. The campus medical center kept telling Zachary that he did not have a serious condition. At one point, they even gave him the cold medicine Robitussin for his symptoms. He now quips that he started i[2]y with the mission statement, “No Robitussin for Brain Cancer.”

	When he was finally diagnosed with brain cancer in December 1995, Zachary learned he had a congenital medulloblastoma (pediatric brain cancer). This brain tumor is classifi ed as a primitive neuroectodermal tumor (PNET) and originates in the cerebellum, which controls balance and other complex motor functions. Most pediatric medulloblastomas are diagnosed in children aged <10 years, so Zachary’s situation was extremely rare.

	In January 1996, Zachary had an hour-long craniotomy to remove his tumor, which he described as “the size of a golf ball.” He additionally received 33 treatments of craniospinal radiation, but refused the recommended chemotherapy.

	Zachary’s doctors wanted to give him chemotherapy, but in his view the treatment offered a limited benefi t for an unacceptable risk. His physicians told him the chemotherapy would increase his 5-year survival chance by 5% (50% to 55%), but would also increase his risk of developing peripheral neuropathy, a nerve condition that would effectively end his piano playing. Unwilling to give up on his passion, Zachary rejected the chemotherapy and never looked back.

	The radiation treatment, however, left Zachary physically and emotionally devastated. At one point, he was taking 17 medications. “I had every [side effect] you could possibly imagine,” Zachary said. With the dearth of resources and support groups available to AYA survivors, Zachary was lost and unsure how to move on with his life. “I looked different in the mirror; I was impotent for 2 years; I didn’t understand how to talk to people,” Zachary said.

	Zachary was eventually able to rediscover and redefi ne himself through his music. He rehabilitated his left hand and performed a concert only 1.5 years after his cancer diagnosis. Starting with that performance, he renamed himself Matthew Zachary (Zachary is his given middle name, not his last name), saying, “I couldn’t deal with being myself.”

	Renaming himself and restarting the piano allowed Zachary to regain control over his life. “I was able to take back what cancer took away. I could own what happened to me because I fi nally had a legacy— I was able to play piano again.” Zachary eventually performed a series of concerts and released several albums. He played 2 songs at NCONN 2010, both of which earned standing ovations. Now married with twin children, Zachary shares his story to raise awareness of disparities in AYAs with cancer. He started i[2]y to help AYAs avoid the isolation and helplessness of his cancer experience.

	During his treatment, Zachary realized the cancer care system was ill-equipped to address AYAs’ unique needs. His pediatric oncologists were used to treating children, so they would speak to his parents instead of him. Additionally, the atmosphere and lack of peer support in the pediatric facility left Zachary feeling extremely isolated. “I [was] in a room with squeaky toys [and] cows on the ceiling— not okay!” Zachary told NCONN attendees.

	Zachary founded i[2]y in 2007 to help create a new reality for AYAs with cancer. i[2]y ensures young adults affected by cancer can access the resources and support they need. The progressive enterprise tailors its message, content, and events to the social and cultural values of young adults. Often infusing Zachary’s irreverent humor and love of music, i[2]y’s catchphrase is “stupid cancer,” which Zachary devised by wondering, “What would Homer Simpson say if he were diagnosed with cancer?” To support AYAs, i[2]y provides both offl ine and online resources.

	i[2]y hosts community outreach events called “Stupid Cancer Happy Hours” to allow AYAs to have fun with their peers. Past events include film screenings, book signings, tweetups, bowling nights, scavenger hunts, golf outings, bar crawls, weekend retreats, roofdeck parties, wine and cheese events, BBQ fundraisers, and Halloween costume balls.

	“Stupid Cancer Boot Camps” are educational workshops that focus on specifi c issues relevant to AYAs with cancer. The events are often conducted in collaboration with local cancer centers or franchises of national cancer organizations. Previous Boot Camps include Progress/Gaps in Young Adult Biology; Clinical Trials in Young Adults; Social Media and Health Technology Advocacy; Employment, Legal and Disability Rights; Navigating Health Insurance; Fertility, Relationships and Sexuality; and Grassroots Activism and Legislation.

	This international conference brings together AYAs affected by all cancers. The gathering unites >20 advocacy, research, and support groups, and fosters an AYA global support network. NCONN will be speaking at the 4th Annual OMG! Summit (www.omgsummit. org/2011), which will take place in New York City on April 16 and 17, 2011.

 is a live talk radio Webcast that gives a voice to the young adult cancer movement. Zachary co-hosts the program with young adult cancer survivor Lisa Bernhard, i[2]y’s vice president of Marketing and Media Development, and formerly an Entertainment Correspondent for FOX News and Deputy Editor of TV Guide. New episodes air live on Mondays at 8 pm Eastern Standard Time.

	The show covers cancer issues related to multiple topics, including politics, healthcare, the environment, social media, entertainment, and education. Some of the previous episode titles were “Breast Cancer and the Environment,” “Stupid Lung Cancer,” “Advocacy Innovation,” and “Showtime’s 

.” NCONN’s president, Sharon Francz, and vice president, Rebecca Trupp, were guests on 

’s November 1, 2010, episode, entitled, “Insurance and Navigation.” This broadcast and all other previous shows can be downloaded on the program’s Website.

	i[2]y’s Website aggregates the available resources for AYAs and provides an online support network. The “How Can We Help You” directory on the home page provides links to resources offering social, fi - nancial, legal, and employment support. The ongoing conversations in “The Stupid Cancer Forums” allow AYAs to communicate and support each other. “The Stupid Cancer Blog” provides continuous updates of the young adult cancer movement. The site’s “Get Involved” section allows AYAs to start participating in i[2]y through a mailing list, Facebook, Twitter, iTunes podcasts, wristbands, local i[2]y chapters, and more.

	Despite its brief existence, i[2]y already boasts an impressive list of achievements:

 magazine named i[2]y’s site one of the “50 Best Websites”

	• i[2]y will soon have >10,000 Facebook friends

 one of the “Best Health Blogs of 2010”

	• Actor Zac Effron has become a spokesperson for i[2]y.

	Beyond its own success story, i[2]y’s advocacy has contributed to tremendous advances for young adults with cancer:

The Journal of Adolescent and Young Adult Oncology

) is launching this spring. This groundbreaking publication will foster interdisciplinary collaboration on research and education in AYA oncology. 

’s editor-in-chief, Leonard S. Sender, MD, is also the chairman of the board of directors of i[2]y. The journal’s content will include original peer-reviewed articles, review articles, highlights of clinical trials relevant to AYAs, case studies with AYA-impact enhancement, advocacy group spotlights, pharmacology highlights, editorials and perspectives, provocative roundtable discussions, and news bites.

	• i[2]y is working to create a continuing medical education program in AYA oncology that would be institutionalized through the NCI

	• Support is growing for the young adult cancer clinic model, whereby in addition to pediatric and adult cancer hospitals, there would also be AYA hospitals

	• The International Charter of Rights for Young People With Cancer is a patients’ bill of rights for young adults with cancer. The Charter hopes to establish an international standard of cancer care for AYAs. You can sign the charter on the organization’s Website.

	• The Leukemia and Lymphoma Society now offers a non—disease specifi c young adult support platform

	• Advances in genomics and stem cell research are exploring the contribution of biological factors to the outcome differentials in the AYA versus the pediatric and adult populations. The young adult cancer movement supports increased tumor banking to support research in these fields.

At NCONN 2010, Matthew Zachary, musician, brain cancer survivor, and founder of the I'm Too Young For This! Cancer Foundation (i[2]y) discussed empowering young adults with cancer. 

I'm Too Young for This!

 Drugs Advisory Committee (ODAC) voted 12 to 1 against maintaining bevacizumab’s (Avastin’s) approval for treatment of breast cancer. The decision follows the FDA’s submission of a report to ODAC suggesting bevacizumab is not as effective in breast cancer as previous studies had indicated and is associated with more serious side effects than similar treatments.                                                                                                                                               Although the FDA will most likely revoke bevacizumab’s breast cancer indication, the agency has overruled ODAC recommendations in the past. In 2008, the FDA’s initial approval of bevacizumab for breast cancer came despite ODAC’s 5 to 4 vote against it. Bevacizumab even received accelerated approval, with full approval predicated on positive data from the two additional studies being conducted by Genentech, the drug’s maker; however, as ODAC’s vote indicates, data from those studies showed that overall survival and tumor shrinkage are not as great as earlier studies demonstrated. The FDA’s decision will not affect bevacizumab’s other approved indications.

 received FDA clearance for its ARCHITECT HE4 (human epididymis protein 4) chemiluminescent microparticle immunoassay, which helps monitor recurrence and progression of ovarian cancer. HE4 is overexpressed by some patients with ovarian cancer, and a recent study by Hellstrom et al found it had the highest sensitivity and specificity among ovarian cancer biomarkers.                                                                                                                                                      CA125, the biomarker commonly used to track recurrence or progression, is not expressed in 20% of ovarian cancer cases. Research also indicates HE4 can improve earlystage ovarian cancer detection, which would improve survival rates.

 to conduct a priority review of denosumab (Prolia) for the treatment of cancer-related bone damage. Denosumab, which has a different mechanism of action from currently approved bisphosphonates, was approved last year as a treatment for postmenopausal women at risk of osteoporosis. Amgen, the manufacturer of denosumab, said a decision is expected by November 18.

, an experimental drug by Keryx, was granted orphan drug status by the FDA in neuroblastoma after positive data on its safety and efficacy from a phase I trial. Only 650 new cases of neuroblastoma are reported each year, and there are no approved treatments specifically for this cancer. Perifosine, an Akt inhibitor, already has an orphan-drug designation for multiple myeloma and refractory advanced colorectal cancer. Phase III trials are ongoing for perifosine in these malignancies.

 the safety of gonadotropin-releasing hormone (GnRH) agonists, testosterone-suppressing medications primarily used to treat prostate cancer. Ongoing analyses have connected GnRHs to increased risk of diabetes, heart attack, stroke, and sudden death. While the FDA does not recommend stopping GnRH use, it wants clinicians and patients to be aware of the potential side effects. The agency recommends close monitoring of patients at risk for cardiovascular disease and diabetes who are receiving androgen-deprivation therapy with Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, or Zoladex.

 two generic formulations of anastrozole, sold as Arimidex by AstraZeneca. Israelbased Teva Pharmaceutical and the West Virginia company Mylan Inc. will each be selling a generic version of the hormonal therapy, approved as an adjuvant therapy in postmenopausal women with breast cancer.

 to discuss regulation of genetic tests used to diagnose disease. The agency is particularly concerned about tests marketed directly to consumers. The FDA has already warned companies selling genetic screening tests and tests designed to predict drug response to consumers that the kits appear to be medical devices and therefore require the agency’s approval. The FDA is also considering subjecting laboratory-developed tests that predict the risk of cancer recurrence to an approval process. The American Clinical Laboratory Association said it is concerned applying medical-device regulations to laboratory tests might hinder development.

Summer FDA Updates

	The FDA approved Tasigna (nilotinib) as a first-line treatment for patients with newly diagnosed Philadelphia— chromosome positive (Ph ) chronic myeloid leukemia (CML), the first new drug approved for this indication in nearly a decade. The decision follows a priority review that primarily considered data from the ongoing ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph CML Patients) study. According to 24-month data from the ENESTnd trial, nilotinib is

	more effective and faster at inducing response than imatinib (Gleevec), the current gold standard for newly diagnosed CML.

	For phase III of ENESTnd, an open-label, multicenter trial, researchers accrued 846 adult patients with previously untreated CML. Patients were randomized 1:1:1 to either 300 mg (n = 282) or 400 mg (n = 281) of nilotinib twice daily or 400 mg (n = 283) of imatinib once daily, with 5 years of follow-up. The primary outcome measure was the rate of 12-month major molecular response (MMR). The main secondary endpoint was the rate of cytogenetic response (CCyR) at 12 months. Researchers published 12-month data in the New England Journal of Medicine in June. At the 2010 American Society of Clinical Oncology meeting in

	Chicago, Illinois, 18-month data were presented, along with 24-month data for a small subset of patients.

	The 12-month MMR rates were 44% and 43% for the 300 mg and 400 mg nilotinib arms, respectively, nearly double the imatinib cohort’s 22% MMR rate. CCyR rates at 1 year were 80% and 78% in the 300 mg and 400 mg cohorts of nilotinib, respectively, compared with 65% for the imatinib arm. “Certainly nilotinib is a better drug than imatinib. I would like to start all patients on nilotinib therapy just to lower the risk of progression of disease that can occur in the first 2 to 3 years of therapy,” said lead investigator Giuseppe Saglio, MD. Both treatments were well tolerated at 12 months, with adverse events causing discontinuation for 5% of patients in the 300-mg nilotinib arm, 9% of patients in the 400-mg nilotinib arm, and 7% of patients in the imatinib arm. Patients receiving imatinib were more likely to experience gastrointestinal effects and edema, whereas the nilotinib cohorts had higher rates of dermatologic events and headache. Only 2 patients on nilotinib had disease progression to accelerated phase or blast crisis, compared with 17 patients treated with imatinib. No one in the study experienced sudden death related to treatment.

	Nilotinib’s superior efficacy held up at 18 and 24 months. MMR rates at 18 months were 69% and 63% for the smaller and larger dose nilotinib cohorts, respectively, compared with 36% for the imatinib group. At 24 months, MMR rates in the 300 mg and 400 mg nilotinib arms were 86% and 88%, respectively, compared with 48% in the imatinib arm. From 12 to 18 months, the gap in CCyR rates between nilotinib and imatinib closed slightly, with 85% and 82% rates for the 300 mg and 400 mg nilotinib arms, respectively, versus 74% for the imatinib cohort (P <.001 and P = .017 for the two comparisons, respectively). The two treatments continued to be well tolerated at 18 months, with discontinuation rates of 7% for the 300 mg nilotinib group, 11% for the 400 mg nilotinib group, and 9% for the imatinib cohort. According to Saglio, the goal now is to “…achieve complete molecular remission and to have the possibility to discontinue the treatment…in the highest percentage of patients that we are treating.”

The FDA approved Tasigna (nilotinib) as a first-line treatment for patients with newly diagnosed Philadelphia- chromosome positive (Ph ) chronic myeloid leukemia (CML), the first new drug approved for this indication in nearly a decade. 

Tasigna Moves to the Front-Line in CML

	The FDA approved the injectable drug Jevtana (cabazitaxel), a microtubule inhibitor, in combination with prednisone as a second-line therapy for men with advanced castrate-resistant prostate cancer (CRPC). Cabazitaxel is indicated for patients whose disease is resistant to docetaxel and standard hormonal treatments. The pivotal trial considered by the FDA demonstrated that cabazitaxel extended survival by ~2.5 months over standard chemotherapy. In a press release, the principal investigator for the North American arm of the trial, Oliver Sartor, MD, Plintz Professor for Cancer Research at Tulane Medical School, New Orleans, said, “Jevtana will help fill a critical treatment gap, since it is the first treatment approved for patients with this stage of metastatic hormone-refractory prostate cancer.”

	Sartor, a lead investigator for the multinational phase III TROPIC study, presented data on cabazitaxel at the 2010 American Society of Clinical Oncology meeting in Chicago, Illinois. TROPIC randomized 755 men with metastatic CRPC who failed on docetaxel chemotherapy to cabazitaxel (n = 378) or mitoxantrone (n = 377). Both cohorts received treatment every 3 weeks for 10 cycles, as well as 10 mg of prednisone daily.

	Patients receiving cabazitaxel experienced a mean survival of 15.1 months compared with 12.7 months for the mitoxantrone arm (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.61-0.84). Researchers also found that men in the cabazitaxel cohort had 14.4% tumor shrinkage compared with a 4.4% reduction for those receiving mitoxantrone (P = .0005), although no patients experienced complete response. Further positive data for patients receiving cabazitaxel included a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.59-0.83; P <.0001).

	Approximately 5% of men receiving cabazitaxel suffered treatment-related deaths. Grade 3 or higher neutropenia afflicted almost 82% of men receiving cabazitaxel versus 58% taking mitoxantrone. Leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia, were each experienced by at least 5% of patients in the cabazitaxel arm, with renal failure occurring in a small number of patients. Researchers urged proactive monitoring and prompt treatment of all adverse events.

The FDA approved the injectable drug Jevtana (cabazitaxel), a microtubule inhibitor, in combination with prednisone as a second-line therapy for men with advanced castrate-resistant prostate cancer

Jevtana Approved for Advanced Prostate Cancer

	In the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) phase III study involving patients with pancreatic neuroendocrine tumors (NET), progression-free survival (PFS) in patients treated with everolimus (Afinitor) was more than 6 months longer than for patients taking placebo (11.0 mo vs 4.6 mo, respectively). Data also revealed a 65% reduced risk of cancer progression for patients in the everolimus cohort (hazard ratio, 0.35; 95% confidence interval, 0.27-

	“Novartis plans to submit worldwide regulatory filings [for a NET indication] in 2010, based on results from the RADIANT-3 study,” said David Lebwohl, MD, vice president and global program head for Afinitor in the Oncology Global Development group at Novartis Oncology. If approved, everolimus would become the first mTOR inhibitor for advanced pancreatic NET, a rare cancer with few therapeutic options and a median overall survival (OS) of 24 months.

	The RADIANT-3 prospective, double-blind, parallel group, multicenter study randomized 410 patients with advanced pancreatic NET to 10 mg of oral everolimus or placebo daily Afinitor Active in Pancreatic NET until tumor progression. Following randomization, patients were monitored with CT scanning and MRI approximately every 12 weeks until progression. The primary endpoint was time without tumor growth; secondary endpoints included objective response rate, OS, and levels of biomarkers.

	The adverse events pattern in the everolimus arm paralleled prior research results. Patients on everolimus experienced stomatitis (53.9%), rash (52.5%), diarrhea (46.6%), fatigue (43.6%), edema peripheral (35.8%), nausea (31.9%), headache (29.9%), pyrexia (29.4%), decreased appetite (28.9%), vomiting (28.4%), weight loss (27.9%), abdominal pain (23.5%), anemia (22.1%), cough (21.6%) and epistaxis (21.1%).

	Study results were presented at the 12th World Congress on Gastrointestinal Cancer in Barcelona, Spain; researchers said they plan to present additional findings later this year at the 35th European Society for Medical Oncology Congress in Milan, Italy. Afinitor is currently FDA-approved as a secondline therapy for patients with advanced renal cell carcinoma following unsuccessful treatment with sunitinib (Sutent) or sorafenib (Nexavar).

In the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) phase III study involving patients with pancreatic neuroendocrine tumors (NET)

Afinitor Active in Pancreatic NET

Array BioPharma Inc released its financial results for the third quarter of fiscal 2010, reporting $18.4 million in total revenue for the period but a net loss of $15.2 million, or $0.30 per share. The numbers are an improvement over the third quarter of fiscal year 2009, when Array posted revenue of $6.0 million and had a net loss of $29.6 million, or $0.62 per share. At the close of the third quarter, Array had $100.3 million in cash, cash equivalents, and marketable securities, a figure that excludes the $45 million Array will receive during the fourth quarter from its recent partnership with Novartis International AG. 

The agreement licensed Array’s cancer drug ARRY-162, along with similar drugs, to Novartis for a potential $467 million in payments and royalties. News of the partnership initially caused Array shares to spike 35%; however, the increase retreated after Swiss bank UBS downgraded Array’s stock from a rating of “Buy” to “Neutral.” UBS based its assessment on the early development stage of most of Array’s pipeline and Array’s deals with Novartis and Amgen (ARRY-403 for type 2 diabetes) limiting the company’s need for additional partnerships. 

Robert E. Conway, CEO of Array, disagrees with UBS’ value assessment. “Based on our current assumptions, our analysis of the estimated risk-adjusted net present value of [the] potential income from our partnered drugs alone significantly exceeds the current market capitalization of the company,” he said. He pointed out that the recent deals with Novartis and Amgen would “provide Array with $105 million in initial payments, over $1 billion in potential milestone payments, double-digit royalties, and commercial co-detailing rights.” In addition to the substantial benefit Array derives from its multiple partnerships, Conway noted that the company’s primary asset is its proprietary pipeline, which has numerous compounds owned 100% by Array.

Array’s oncology pipeline includes inhibitors of HER2, EGFR, KSP, p38, and Tie-2. Eight abstracts disclosing data from studies of several of these anticancer drugs were presented at the 

American Association for Cancer Research 101

, held from April 17 to 21, 2010, in Washington, DC. 

Array is working with Novartis to develop MEK162 (ARRY-162) and MEK300 (ARRY-300), and other MEK inhibitors. With the maximum tolerated dose of MEK162 now established, Array is proceeding with expansion of a phase I trial in patients with biliary tract cancer, which is taking place at 10 trial locations in North America. The expansion study will be evaluating the pharmacokinetics and pharmacodynamics of the drug, along with tolerability. Array hopes MEK162 will prove successful in multiple indications.

ARRY-520, a kinesin spindle protein inhibitor, is in phase I trials in patients with solid tumors and in phase I/II trials for patients with acute myeloid leukemia and multiple myeloma. Array hopes to complete these trials in the current fiscal year. In a proof-of-concept study, investigators are evaluating the activity and safety of the p38/Tie-2 inhibitor ARRY-614 in a phase Ib/II trial of patients with myelodysplastic syndromes. 

Three phase Ib trials evaluated ARRY-543, an ErbB-family inhibitor, in combination with other agents as a treatment for solid tumors. One looked at ARRY-543 in combination with capecitabine (Xeloda), another with docetaxel (Taxotere), and the third with gemcitabine (Gemzar). Researchers reported that these trials have established the maximum tolerated dose of ARRY-543. They expect to present updated data at a selected conference later this year and are moving forward with plans for a phase II combination trial. ARRY-380 is a HER2 inhibitor being studied in a dose-escalation, phase I trial of patients with advanced cancer.

In addition to the new deal with Novartis on its MEK inhibitors, Array has an arrangement with AstraZeneca to continue development of AZD-6244, a MEK inhibitor being investigated in KRAS-mutated non—small cell lung cancer and BRAF-mutated melanoma. The company reported that AstraZeneca is continuing with two phase II combination trials of AZD-6244 combined with MK-2206, an AKT inhibitor being developed by Merck. 

Array has partnerships with Amgen, InterMune, Eli Lilly, Celgene, and Genentech to develop existing drugs or collaborate on the development of new drugs, not only in oncology but also in diabetes and immune disorders. Array recently estimated the net present value of its partnered and wholly owned programs at more than $800 million.

Array BioPharma Inc released its financial results for the third quarter of fiscal 2010, reporting $18.4 million in total revenue for the period but a net loss of $15.2 million, or $0.30 per share.

Array BioPharma Has No Shortage of Partners

A struggle with cancer is often referred to as a battle. Now, a study reveals patients with cancer and caregivers even experience a condition common to soldiers, post-traumatic stress syndrome. The disorder does not arise from cancer’s primary theater of conflict, the tumor site, but rather from a secondary battlefield, the patient’s wallet. The report, issued by the nonprofit Cancer Support Community (CSC), in conjunction with biotech company Genentech Inc, found the financial burden of cancer costs leaves patients and caregivers vulnerable to anxiety, depression, and other mental health issues. Eighty-one percent of patients and 72% of caregivers surveyed reported “moderate to severe” levels of stress due to financial issues.

According to Joanne S. Buzaglo, PhD, senior director of research at CSC, researchers were surprised by the severity of the condition. “It is hard to imagine, but the levels of post-traumatic stress reported were even greater than that of those who witnessed the terrorist attacks in New York City on September 11 and akin to that of underprivileged, displaced survivors of Hurricane Katrina.”

The study, entitled “Evaluation of the Challenges and Barriers to Accessing Financial Support for Cancer Patient Treatment,” differed from previous research in that it used a standardized measure to analyze symptoms of post-traumatic stress related to cancer costs. Researchers surveyed an ethnically diverse group of 105 patients and caregivers. Over half of the respondents were employed. Twenty-five percent of patients and 18% of caregivers surveyed had household incomes of  <$20,000/y. Ninety-one percent of patients had insurance coverage, with 19% using Medicare or Medicaid. 

For several individuals, the distress arose from an inability to afford medical bills totaling thousands of dollars. Others reported insurance coverage issues, including calendar-year limitations on appointments with specialists. For most, attempting to solve the fiscal crisis only worsened the despair. Many patients began sacrificing their health, skipping medication doses, or selecting inferior, less expensive treatments. Others depleted savings, borrowed money from family or friends, or started working a second job. 

As their fiscal problems mounted and stress levels rose, respondents experienced several barriers to needed assistance. Approximately 50% of patients lacked the funds for mental health support. Nearly half of patients were unaware of financial assistance programs, while others feared they would not qualify for aid or were unwilling to face financial scrutiny. Some were simply too exhausted and overwhelmed from their cancer treatment to pursue assistance. “Those with the greatest economic need often fail to seek out assistance due to the distress they are experiencing,” said Buzaglo.

Those who did seek financial assistance found the Internet and social workers to be the best information sources. Some patients (34%) were enrolled in pharmaceutical or copay assistance programs. For more on the study, go to 

A struggle with cancer is often referred to as a battle. Now, a study reveals patients with cancer and caregivers even experience a condition common to soldiers, post-traumatic stress syndrome.

Jason M. Broderick