OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Despite misgivings among physicians, the Internet is growing as a source of health information for patients. The FDA’s recent handling of a potential link between breast implants and a rare form of cancer serves as a textbook example of how to communicate an important public health message without promoting hysteria.

	The role of the Internet as a source of health information is well established—and growing. While the data are perhaps not representative of the entire population in this country, a survey in Consumer Reports in March revealed that 61% of the magazine’s subscribers search the Internet for information regarding their own medical condition.

	Yet while the public is clearly comfortable using the Internet for this purpose, the medical community has concerns regarding the overall quality and usefulness of health data available through this source. For example, in the same survey noted above, only 8% of physicians said the Internet was “very helpful” for their patient population.

	However, no matter what objective data show or subjective feelings indicate about the current state of affairs associated with Internet-based health-related communication, there is little disagreement regarding the remarkable potential for this rapidly evolving strategy to serve a vitally relevant role in providing highly meaningful, valid, and easily understood information to individual patients and all of society.

	Consider, for a moment, the ability of public health authorities to inform both the public in general, or a specifi c patient population in particular, about a complex matter that may require action, even though the message itself may result in understandable, but perhaps excessive, anxiety and concern that lead to more extreme actions than warranted based on existing evidence.

	A specifi c and highly relevant recent example of the effective use of Internet-based communication by a public health agency in this setting is found in the FDA’s discussion of its preliminary assessment of the potential development in women with breast implants of a very rare cancer, anaplastic large cell lymphoma (ALCL).

	In a January 26 press release, the FDA described the preliminary findings of a “possible association between saline and silicone gel-filled breast implants and anaplastic large cell lymphoma.” The agency accompanied the announcement with a “Consumer Update” brochure, available in PDF format for downloading, and relevant background links (

	The material was presented in a well-organized manner that a nonmedical and nonscientific audience should have easily understood. In addition, the authors took great care to explain both the clinical significance of the finding of this cancer, but also the rarity of the condition. They note, for example, that “about 60 cases of ALCL in women with breast implants worldwide” have been reported among “an estimated 5 million to 10 million women worldwide” who have breast implants. However, even though quite rare in women with breast implants, the FDA document noted that “ALCL located in breast tissue is found in only about 3 out of every 100 million women nationwide without breast implants.”

	Finally, and perhaps most importantly, very specific recommendations and action items are presented to the public and women with breast implants. The news release states: “There is no need for women with breast implants to change their routine medical care and follow-up. ALCL is very rare; it has occurred in only a very small number of the millions of women who have breast implants.”

	Additionally, the FDA uses this document and an online drug-monitoring strategy to encourage healthcare professionals “to report all confirmed cases of ALCL in women with breast implants to MedWatch, the FDA’s safety information and adverse-event reporting program.” Thus, at the same time the FDA is providing up-to-date objective data and appropriate reassurance to women with breast implants, it is continuing to encourage healthcare professionals, and patients themselves, to provide additional data upon which future health-related recommendations and communications can be based.

	Public health agencies should be encouraged to expand substantially their efforts to communicate electronically with patients, the public, and healthcare professionals. The strategy that the FDA employed in this communication regarding ALCL in women with breast implants is an excellent example of how this can be accomplished effectively.

	Maurie Markman, MD, editor-in-chief of OncLive, is vice president of Patient Oncology Services and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania.

Articles

Despite misgivings among physicians, the Internet is growing as a source of health information for patients.

Right Public Health Message Serves Up Facts Without Panic

	Enzyme Inhibitor Tagged as Ovarian Drug Candidate

	NKTR-102, a next-generation topoisomerase I inhibitor, has been granted orphan drug status by the FDA for the treatment of women with ovarian cancer, according to Nektar Therapeutics, the San Francisco, California, company developing the drug.

	Nektar made the announcement April 21 amid an ongoing phase II study of the effectiveness of NKTR- 102 in patients with platinum-resistant ovarian cancer and disease progression after pegylated liposomal doxorubicin therapy. Investigators are seeking to enroll 125 participants in that study, and plans also are underway for a phase III study.

	Last year, promising phase I data presented at the American Society of Clinical Oncology annual meeting indicated that NKTR-102 demonstrated signifi cant antitumor activity, with a confi rmed response rate of 11% in patients with refractory solid tumors.

	Nektar describes NKTR-102 as having a unique profi le that uses a releasable polymer conjugate technology platform the company invented. NKTR- 102 appears to function as an improved form of the chemotherapeutic agent irinotecan, allowing the active drug to be maintained at a continuous concentration instead of clearing from the body within a few hours of dosing, as the standard therapy version does.

	In addition to ovarian cancer, Nektar is investigating NKTR-102 for patients with metastatic breast cancer, and as second-line and combination therapy for patients with colorectal cancer.

	The orphan drug designation, aimed at promoting the development of medicines for diseases that affect fewer than 200,000 people, grants a company US market exclusivity for 7 years.

	Olaparib in Combination With Carboplatin for Refractory or Recurrent Women’s Cancers

Women ≥18 years of age who have breast, ovarian, uterine, or cervical cancers that have not responded to standard treatment. Men ≥18 years of age who have metastatic breast cancer and a 

The objective of this study is to determine the safety and effectiveness of combined carboplatin and olaparib as a treatment for gynecologic or breast cancer. The trial will determine a safe dose of olaparib tablet with carboplatin, estimate the pharmacokinetic and pharmacodynamic effects of 2 schedules of olaparib and carboplatin by using peripheral blood mononuclear cells, and determine the schedule-associated safety of olaparib and carboplatin in women’s cancers.

	State-of-the-Art Treatment for Triple-Negative Breast Cancer

February 12, 2012 This activity is intended for oncologists, surgeons, pathologists, obstetrician/gynecologists, nurses, and other healthcare professionals who screen, diagnose, and treat women with breast cancer. The goals of this activity are to review the epidemiology and diagnosis of triple-negative breast cancer (TNBC) and to review current as well as any new and novel treatments. Another goal is to identify practice changes based on key developments that may help to improve quality of life and outcomes in patients with TNBC. Also discussed are screening practices, surgery, and epidemiology of TNBC.

Breast cancer resources gathered from across the web including a news brief, patient education, clinical trials and CME/CE

Disease States: Breast Cancer

	This photo depicts the LumaGEM™ Molecular Breast Imaging (MBI) System in use.

	Breast imaging technology has evolved in recent years, and although the mammogram remains the gold standard for screening, researchers are excited about the possibilities of molecular breast imaging (MBI), aimed primarily at women with harderto- analyze dense or fatty tissues.

	A research team at the Mayo Clinic has developed a gamma-radiation system in which a patient is injected with a radioisotope (technetium 99m sestamibi), and then images are taken using cadmium zinc telluride (CZT) technology.

, the researchers said that the use of their MBI technique with mammography “significantly increased detection of node-negative breast cancer in dense breasts by 7.5 per 1000 women screened (95% confi dence interval [CI], 3.6—15.4).” At the same time, they noted that the gamma technology would have to reach equivalent performance levels with lower doses of radiation if it is to make an impact on clinical practice (2011:258:106-118).

	The trial involved 936 asymptomatic patients >40 years old who had extremely dense breast tissue on previous mammograms and additional risk factors. In all, 11 participants had cancer: 1 was detected with mammography only, 7 with gamma imaging only, 2 with both combined, and 1 with neither method.

	“The ratio of the number of patients with breast cancer per number of screening examinations with abnormal findings was 3% (3 of 88) for mammography and 12% (9 of 73) for gamma imaging,” the investigators reported.

	A new Mayo Clinic study that will compare mammography with low-dose MBI in 2400 women is underway, according to Gamma Medica Inc, the company bringing the MBI technology to market. In April, the Northridge, California, company said preliminary results from 440 women studied thus far indicate cancers were diagnosed in 6 patients, with MBI leading to detection in 5 patients, while none was detected through mammography.

	The LumaGEM™ Molecular Breast Imaging (MBI) System has been cleared by the FDA.

Breast imaging technology has evolved in recent years, and although the mammogram remains the gold standard for screening, researchers are excited about the possibilities of molecular breast imaging

Searching for Sharper Images in Breast Screenings

	It’s a question that people frequently ask patients with cancer: ”What can I do to help?” The Leukemia & Lymphoma Society (LLS) has decided to answer that question through collaboration with Lotsa Helping Hands, a group that uses the Internet to build communities of volunteer caregivers.

	The society offers a page on its Website where family, friends, and colleagues can create a community of helpers for a particular patient. The idea is to make the main caregiver’s job more manageable by using a private online calendar to organize the delivery of meals, rides to appointments, and other daily tasks. “Lotsa Helping Hands is a wonderful resource. It is an important partnership for LLS because we are committed to helping families manage the disruption of their living needs when a loved one has blood cancer,” said Hildy Dillon, LLS senior vice president of patient services, in a press release.

	Mastering the Basics of a Neutropenic Diet

	For patients with lower-than-normal levels of neutrophils, a special diet may be necessary. The neutropenic diet is designed to help protect a patient from bacteria and harmful organisms sometimes found in food and drinks. Under the “Managing Your Cancer” tab on the Leukemia & Lymphoma Society’s Website, patients can access basic guidelines and tips for staying healthy during treatment. This diet in particular advises patients to avoid uncooked vegetables, rare or raw meat, eggs and fish, soft mold-ripened cheeses, and well water. It suggests consuming only thoroughly cooked meats, pasteurized dairy products, tap water, and vacuum-packed lunchmeats.

	Diagnostic Study of Patients With Acute Lymphoblastic Leukemia or Acute Promyelocytic Leukemia

 Cancer and Leukemia Group B, National Cancer Institute

 This study aims to use leukemia-specific markers in bone marrow specimens to evaluate the expression of novel genes or micro-RNAs implicated in disease pathogenesis and treatment response. The findings will be correlated with novel treatment approaches and other biological and clinical prognostic features. Investigators are seeking 450 trial participants over 5 years.

	Non-Hodgkin Lymphoma Forum— Addressing Clinical Challenges in Community Practice

	The goal of this CME activity is to identify key challenges when treating patients with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, or Waldenström macroglobulinemia in community practice. Participants also will learn the ways in which community practitioners can effectively apply the latest research data to optimize treatment of patients with these diseases.

Hematologic cancer resources gathered from across the web including a news brief, patient education, clinical trials and CME/CE

Disease States: Hematologic Cancers

	In order to learn more about the genetic causes of non-Hodgkin lymphoma (NHL), scientists are going to the dogs—literally.

	Researchers at North Carolina State University used canines as genetic models for studying lymphomas based on the theory that analyzing the restricted genetic variation of purebred dogs would enable them to pinpoint NHL-associated aberrations in chromosomes that are difficult to distinguish in humans.

	To conduct their study, investigators surveyed 150 non-random canine NHL cases. Thomas et al reported in Leukemia & Lymphoma that they found limited genomic instability when compared with data from humans, and no evidence for CDKN2A/B deletion in canine B-cell NHL. (Published online ahead of print March 7, 2011. doi:10.3109/1042819 4.2011.559802.)

	“‘Genomic recoding’ of canine NHL data into a ‘virtual human’ chromosome format showed remarkably few regions of copy number aberration (CNA) shared between both species, restricted regions of dog chromosomes 13 and 31, and human chromosomes 8 and 21,” researchers said in their abstract.

	They said more clues about NHL genes in humans might be gleaned by further study of the “less complex association between CNAs and tumor pathogenesis in canine patients.”

Researchers at North Carolina State University used canines as genetic models for studying lymphomas

Canine DNA Yields Clues to Human Lymphomas

A Conversation With Joyce A. O’Shaughnessy, MD

	As a child in Beverly, Massachusetts, Joyce Ann O’Shaughnessy enjoyed science and her home chemistry set. Still, she didn’t give much thought to pursuing the subject beyond the confines of her school—until she faced a tragedy.

	After her youngest sister, Teri, was diagnosed with leukemia, 14-year-old O’Shaughnessy demonstrated the seriousness and determination that have since shaped her career as a physician and cancer researcher. Frustrated by her inability to help, the teenager vowed to fight cancer by becoming a doctor.

	When Teri died 5 years later, at the age of 10, O’Shaughnessy was a freshman biology student at Holy Cross College in Worcester, Massachusetts. She reacted to the loss by reinforcing her commitment to fight the disease.

	“I wanted to immediately start doing research, but as a 19-year-old that wasn’t as common back then,” O’Shaughnessy recalled. “I went to the dean and said, ‘I need to start doing cancer research. Can I do it here, or do I need to transfer to a big university?’ ”

	The dean provided funding to support the fledgling researcher, who studied tumor virology and wrote a senior thesis on leukemia before going on to earn a medical degree, cum laude, from Yale University and launching a career devoted to fighting breast cancer.

	Since 1997, O’Shaughnessy has worked as a medical oncologist within a practice of more than 400 physicians, Texas Oncology, and has served as co-chair for breast cancer research at US Oncology, a physician practice management company that cares for about 20% of the nation’s cancer population and brings oncologists together to do clinical research. Based in Dallas, O’Shaughnessy is also the Celebrating Women Endowed Chair in Breast Cancer Research at the Baylor- Charles A. Sammons Cancer Center at Baylor University Medical Center.

	In the 25 years since she began that first research project, O’Shaughnessy has treated thousands of patients with breast cancer while evaluating new therapeutic strategies to fight the disease. Her accomplishments include designing and leading investigations of capecitabine and gemcitabine, cytotoxic agents that were approved by the FDA about a decade ago and are now among those most widely used in treating breast cancer. O’Shaughnessy also led recent studies of iniparib, a novel drug for patients with metastatic triple-negative breast cancer and other cancers.

	“Breast cancer is, in a sense, a very hopeful disease—we have a lot of success in treating breast cancer, and this spurs you on to crack the code of the breast cancers that are not yet curable,” O’Shaughnessy said. “There are many different subtypes, and clinician investigators are working to match patients’ genotypes to the most promising therapies for them.”

ONC: You regularly plan and oversee clinical trials designed to improve care for breast cancer patients. What are some of your current projects? 

I’m the principal investigator on a US Oncology trial being done in collaboration with the Translational Genomics Research Institute (TGen) and Life Technologies within which TGen is conducting whole genome sequencing on tissue obtained from metastatic triple negative breast cancer patients.

		The objectives of the study are to determine the key driving mutations in these patients’ cancers, and to then refer patients to the appropriate clinical trials to receive treatment with agents that target these key driving mutations. It’s an important effort in that there has been only one patient whose metastatic triple negative breast cancer has been fully sequenced and published, and it is critical that we develop an understanding of the main molecular abnormalities in these aggressive cancers.

		In addition, I’m serving as a co-investigator in a US Oncology trial known as the TC-TAC trial. TAC is a standard chemotherapy regimen for high-risk early breast cancer patients: docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan). But for HER2-negative breast cancer, which is this trial’s focus, we really don’t know if patients need the doxorubicin, which can cause congestive heart failure and leukemia. We’re conducting this large randomized phase III trial to try to answer the question of whether doxorubicin is needed in treating ER or triple negative breast cancers. If the answer is no, we can give patients the same chemotherapy regimen without doxorubicin and get equally good results with less toxicity.

	During a typical week, O’Shaughnessy discusses the design of diagnostic and therapeutic studies with clinical research specialists across the country, considering: biologic mechanisms; which patients, and with which forms of breast cancer, should be included in trials; and whether compounds should be tested as single agents or in combination with other treatments. After helping to develop new agents for the treatment of metastatic breast cancer, O’Shaughnessy often works to bring the therapies to patients with less-advanced forms of the disease, in the preoperative or adjuvant setting.

	O’Shaughnessy also spends 2 days a week treating breast cancer patients while peppering her schedule with visits to research, investigator, and advisory meetings, and medical conferences, along with opportunities to teach practicing medical oncologists.

	“It’s what I want to do,” O’Shaughnessy said. “I’ve chosen not to dedicate time now to hobbies that could be otherwise dedicated to pushing back the frontiers of breast cancer. I really love it, and I wouldn’t want it any other way.”

	More than a decade ago, O’Shaughnessy made signifi cant contributions to breast cancer care by helping to design and oversee clinical trials for gemcitabine (Gemzar) and capecitabine (Xeloda), leading to FDA approval of the drugs that have improved outcomes for many breast cancer patients. The treatments, part of a class of cytotoxic agents called antimetabolites, which stop the growth of cancer cells by preventing the production of DNA and RNA, are also used in other types of cancer, and are being investigated in early breast cancer.

	Over the years, the researcher was also involved in the original clinical trials of paclitaxel (Taxol), a mitotic inhibitor; FLAC chemotherapy (treatment with a combination of 5-fl uorouracil, leucovorin, doxorubicin, and cyclophosphamide); a combination of lapatinib and trastuzumab to treat metastatic HER2-positive breast cancer; and bevacizumab (Avastin), which she believes should remain a treatment option for metastatic breast cancer patients, despite a 2010 recommendation by the FDA that the breast cancer indication be eliminated from the Avastin label.

	Recently, O’Shaughnessy has been at the hub of another groundbreaking project, serving as lead investigator in clinical trials of iniparib. The initial trial caused excitement because of the proposed cutting-edge mechanism of the targeted treatment, which is thought to work by inhibiting PARP, or poly (ADP-ribose) polymerase, leaving cells unable to repair DNA after they are hit by chemotherapy.

	“Synthetic lethality is the concept,” O’Shaughnessy said. “You figure out from a synthetic standpoint what problem the cancer already has, and what therapeutic inhibitor you can add to cause a lethal event. The preliminary data from PARP inhibitor trials have launched a new field of research.”

	O’Shaughnessy’s initial iniparib trial also drew attention within the oncology community because it tested the drug’s potential in patients with triple-negative breast cancer (TNBC), a condition that accounts for 15% to 20% of all breast cancers and is associated with poorer outcomes. TNBC arises when tumors lack receptors for estrogen or progesterone and do not overexpress the protein HER2. That makes hormonal therapies such as tamoxifen and targeted therapies such as Herceptin ineffective, leaving chemotherapy as the standard treatment.

	In a phase II study, the results of which were announced in June 2009, O’Shaughnessy reported that treatment with iniparib, in combination with gemcitabine and carboplatin, significantly improved overall survival in women with metastatic TNBC.

	But in early 2011, the confirmatory phase III trial results showed that while iniparib benefited TNBC patients in the second- and third-line settings, it had not brought about anticipated increases in overall and progression-free survival in patients receiving fi rst-line therapy, nor in the overall population.

	“It’s a puzzle to us at this time why we did not see that same big benefit in first-line patients,” O’Shaughnessy said. “We’re doing clinical and biomarker analyses to understand the patient populations in the two trials to see if there are differences, so the way forward is under very active discussion. It’s planned that there will be additional studies to follow up on this phase III trial in breast cancer. We are very committed to finding out who benefits and who doesn’t, and doing trials specifically in those patients we believe will benefit.”

	Ultimately, O’Shaughnessy anticipates that iniparib—also being studied in patients with squamous non-small cell lung cancer, breast, brain, and other cancers&mdash;will be helpful for a specific group of breast cancer patients.

	Similarly, O’Shaughnessy believes that capecitabine, when studied further, will turn out to be most useful in earlystage patients with rapidly growing breast cancers—despite the drug’s failure, last year, to meet all its endpoints in an adjuvant trial of patients with high-risk early breast cancer.

	“If we can prove it, the capecitabine and iniparib trials may demonstrate that a drug can benefit specific patient subgroups even if a study of all patients combined has negative results,” O’Shaughnessy said. “This will help change the treatment paradigm in the sense that, increasingly, we are understanding that these treatments do not work for all patients with breast cancer, since there are several major kinds.”

			Is married; her husband Ed is an attorney

			Has 2 children: 20-year-old Mark, a sophomore at Stanford University, and 18-year-old Tess, a freshman at Princeton University. The two made it into top schools because “we’re hardworking in our family,” O’Shaughnessy said. “The kids are tired of hearing me say that hard work is its own reward.”

			Enjoys visiting her parents, sisters, and extended family in Boston and coastal New Hampshire several times each year

			In 1982, won the Francis Parker Award at Yale Medical School, meaning she was the faculty’s choice for Most Promising Clinician

			Serves as the Celebrating Women Endowed Chair in Breast Cancer Research at Baylor University Medical Center, in Dallas

			Is a member of the oncology advisory boards for J&J, Lilly, GSK, Genentech, Caris Diagnostics, Boehringer Ingelheim, Novartis, BMS, Enzon, and Sanofi

			Sees a trend toward clinical trials becoming smaller and more numerous, due to the growing need to treat specifi c cancer subtypes. The trials will require more central and practice infrastructure, she expects, but will bring greater clinical benefit and scientific insight

			Believes it is crucial for the government to prioritize funding of oncology research and development, despite economic constraints and healthcare reform laws. “Restricting research and development at this time would be to not realize the return on the enormous investment that has been made in cancer science, given the explosive pace of discovery going on in molecular diagnostics and targeted therapeutics,” she said.

	It was early in her career when O’Shaughnessy realized she had a penchant for deciphering the puzzles presented by disease. As a senior at Holy Cross, she was chosen as Fenwick Scholar, entitling her to spend her senior year conducting independent research. Working at the Worcester Foundation for Experimental Biology, O’Shaughnessy studied ultrastructural analysis of human and mouse leukemia.

	“I had a lot of time to read in the library and try to think through problems in tumor virology,” the researcher recalled. “Still, to this day, that’s what I like to do best—read a lot of cancer biology data and try to connect the dots, thinking about my patients’ specific breast cancers.”

	When O’Shaughnessy left Yale, she didn’t immediately have the opportunity to use those skills. Her internship and residency in Internal Medicine at Massachusetts General Hospital didn’t leave time for research.

	Later, as a medical oncology fellow at the National Cancer Institute (NCI) in Bethesda, Maryland, O’Shaughnessy experienced the opposite extreme: She researched to her heart’s content, but had limited patient contact after the clinical training years.

	“Practice is extremely rewarding to me, and I can’t imagine not doing it,” she refl ected. “It’s extremely rewarding to be an individual woman’s advocate, bringing research to her, and making sure she’s getting the best, including the best clinical trials. Also, that’s where you learn all about the disease. There’s no substitute for being there with the patients and seeing which therapies they respond to and matching their natural history phenotypes to their genotypes.”

	Wanting to combine her interests, O’Shaughnessy decided to stay at NCI but pursue clinical and translational research. In 1990, 5 years into her experience there, O’Shaughnessy took a position offered to her by Ken Cowan, MD, PhD, in the Medicine Branch breast cancer research program, and realized she’d found her niche.

	“That brought it all together for me,” she recalled. “It involved clinical and translational science, patient care, teaching, and working with scientists in the lab. It crystallized exactly what I wanted to do.”

	Her current roles offer a similar mix, allowing O’Shaughnessy to “be part of the team of oncologists around the world that are putting together novel combinations of key pathway inhibitors in breast cancer,” she said. “We need to move toward evaluating triplet combinations of pathway inhibitors, and that means understanding individual cancers and the key pathways driving them.”

	Along the way, O’Shaughnessy hopes to spare patients and their families the helplessness she and her family experienced during her sister’s battle with cancer.

	“In addition to my sister’s cancer battle, I made the decision to pursue oncology because I thought that the pathogenesis of malignancy would come to be understood during my lifetime,” O’Shaughnessy said. “I very much wanted to see this unfold, and my expectations are being surpassed.”

As a child Joyce Ann O'Shaughnessy enjoyed science and her home chemistry set. Still, she didn't give much thought to pursuing the subject beyond the confines of her school - until she faced a tragedy.

Attacking the Frontiers of Breast Cancer: A Conversation With Joyce A. O'Shaughnessy, MD

		David M. Sabatini, MD. PhD, is a principal investigator at the Sabatini Lab at the Whitehead Institute for Biomedical Research and associate professor of biology at Massachusetts Institute of Technology (MIT). His research into the mTOR pathway has led to the identification of numerous components of this pathway, as well as its cellular and organismal functions. He is a recipient of the 2009 Paul Marks Prize for Cancer Research, among numerous other distinctions.

		What role does mTOR signaling play in normal cells?

		In normal cells, mTOR is essential for cells to generate and accumulate mass, and therefore grow (ie, increase in size). It is one of the central growth-promoting pathways in all cells.

		How important is it in cancer development?

		mTOR is also a key growth regulator in cancer cells. In addition, there are many cancer-causing mutations (in tumor suppressors and oncogenes) that lead to mTOR activation—so that it is estimated that 60% to 80% of tumors have hyperactive mTOR signaling.

		Are there any currently available mTOR-targeted treatments?

		Yes. The best-known mTOR inhibitor is a molecule called rapamycin, and there are also derivatives of rapamycin that are in clinical use. These molecules are used as immunosuppressants, blockers of coronary vessel restenosis in drug-eluting stents, and as treatments for cancer. They also have potential uses in neurodegenerative diseases.

		Which components of the mTOR pathway do they target?

		They all target the mTOR kinase, which is the central component of the pathway. They are allosteric inhibitors of mTOR.

		What is the future for mTOR signaling in cancer research?

		The key will be to identify which cancers are particularly sensitive to mTOR inhibitors. Currently, we know that many cancers exhibit mTOR hyperactivation, but not all respond equally to mTOR inhibitors. What is most needed is the identification of a cancer-specific mutation that causes cancers to be addicted to mTOR activity.

	The wealth of literature describing the mammalian target of rapamycin (mTOR) features a common analogy: that mTOR is a “master switch,” “central regulator,” or “key integrator” of cell growth and proliferation. Therefore, it is unsurprising to find that aberrant mTOR signaling is implicated in the pathogenesis of cancer and has attracted substantial interest from researchers since its discovery 20 years ago.

	mTOR is a serine/threonine kinase that exists in 2 multiprotein complexes, mTORC1 and mTORC2, defined by the different component proteins bound to mTOR. Both complexes consist of mTOR and the mLST8 and Deptor proteins. mTORC1 also contains the regulatory-associated protein of mTOR (Raptor) and the proline-rich Akt substrate of 40kDa (PRAS40) protein. mTORC2 contains the rapamycin-insensitive companion of mTOR (Rictor), mammalian stress-activated kinase-interacting protein 1 (mSin1), and the protein Protor.

	Rapamycin, available since the mid-1970s, is a naturally occurring inhibitor originally isolated from a strain of the soil bacterium Streptomyces hygroscopicus and was initially used as an immunosuppressive drug. The discovery of 2 yeast genes, TOR1 and TOR2, led to the identification and cloning of mTOR. And, once mTOR was implicated in cancer, researchers turned their attention to the role of rapamycin in cancer development.

	The exact mechanism of rapamycin inhibition remains unclear; it forms a complex with FKBP12 (FK506-binding protein of 12kDa) and mTOR. It is believed that only mTORC1 is infl uenced by rapamycin. However, recent evidence suggests that mTORC2 may also be susceptible to prolonged rapamycin exposure.

	Conserved from yeast to man, mTOR integrates incoming signals from nutrient and energy sensors on the cell surface with activation of cellular machinery to regulate growth and proliferation, ensuring that these processes happen only under appropriate conditions. mTOR receives signaling input from growth factors, hormones (eg, insulin), nutrients (eg, amino acids), cellular energy levels, and stress conditions.

	A principal signaling pathway that activates mTORC1 is the phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) pathway, which is well known for its central role in cell survival and proliferation. In the context of mTOR signaling, activated Akt phosphorylates and inhibits the tuberous sclerosis complex (TSC) and PRAS40, both of which are negative regulators of mTORC1, thereby activating mTORC1.

	Notably, mTORC1 can also be activated via AMPactivated serine/threonine protein kinase (AMPK), a sensor of cellular energy status. The activation of mTORC2 is understood to a far lesser degree, but it is believed to occur exclusively in response to growth factors.

	The best characterized targets of mTOR signaling are ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), both of which regulate protein synthesis. However, mTOR activates a vast range of proteins that regulate many of the “hallmarks of cancer” described by Robert Weinberg in his landmark Cell article in 2000, including cell division, angiogenesis, and cell survival.

	Surprisingly, a direct involvement of mTOR in cancer development has yet to be proven. Researchers have been unable to identify any cancer-driving mutations in the TOR gene, and it is still unclear whether aberrant mTOR activation is required for cancer initiation.

	What is clear is the indirect involvement of mTOR signaling in a plethora of different cancers, via overexpression or loss of upstream activators, downstream targets, and regulators of mTOR activity. The main culprits leading to aberrant mTOR signaling include mutations in PI3K, overexpression of Akt, overexpression or mutation of the TSC complex, many receptor tyrosine kinases, and the mTOR target proteins S6K1 and 4EBP1. In addition, the loss of function of the phosphatase and homolog tensin gene (

) counteracts PI3K function; it is among the most commonly inactivated tumor-suppressor genes in human cancers.

	Overall, aberrant mTOR signaling is estimated to be activated in 60% to 80% of gastric adenocarcinomas, 25% to 45% of hepatocellular carcinomas, and numerous other tumor types, including HER2-positive breast cancer, non-Hodgkin lymphoma, colon cancer, and prostate cancer.

	mTOR Inhibition: Something Old, Something New

	Currently, there are 2 mTOR inhibitors approved by the FDA, both of which are analogs of rapamycin (dubbed rapalogs). They are everolimus (Afinitor), an oral agent dosed once per day, and temsirolimus (Torisel), administered intravenously once per week. Both are approved for the treatment of renal cell carcinoma (RCC): everolimus for refractory, advanced RCC after failed treatment with the receptor tyrosine kinase inhibitors sorafenib (Nexavar) and sunitinib, (Sutent) and temsirolimus for poorprognosis, untreated RCC. In Europe, temsirolimus is also approved for refractory mantle cell lymphoma (MCL) and a third rapalog, ridaforolimus, is approved for RCC.

	Clinical trials of rapalogs are ongoing in a variety of different tumors as single agents and in combination with other therapies. However, despite promising improvements in progression-free survival, overall survival, and overall response rate in RCC and MCL, rapalogs have proven only modestly successful in many clinical trials. In part this reflects the fact that rapalogs do not effectively inhibit mTORC2 and an incomplete understanding of the functions of mTOR and the complex feedback loops in its signaling network. Particularly relevant in respect to the latter is a recently identified negative feedback effect on the PI3K/Akt pathway, suggesting that inhibition of mTOR may inadvertently activate this pathway, thereby promoting growth and survival.

		This illustration depicts a simplified scheme of the mTOR signal transduction pathway

		Campa D, Hüsing A, Stein A, et al. Genetic variability of the mTOR pathway and prostate cancer risk in the European prospective investigation on cancer (EPIC). 

 6(2): e16914. doi:10.1371/journal.pone.0016914.

	In response to the deficiencies of the rapalogs, a second generation of smarter compounds is being developed. Among them are specifi c mTOR inhibitors that target the kinase activity of both mTORC1 and mTORC2, including WYE354 and WYE132 (Pfi zer), PP30 and PP242 (Intellikine), AZD8055 (AstraZeneca), OSI-027 (OSI Pharmaceuticals), and Torin1. These inhibitors have been shown to induce more potent and durable inhibition of mTOR.

	In order to circumvent the activation of feedback loops that may preclude tumor responsiveness to mTOR inhibition, dual inhibitors of mTOR/PI3K have also been developed, including BEZ235 (Novartis), XL765 (Exelixis), GDC-0980 (Genentech), PF-04691502 (Pfizer), and PF- 05212384 (Pfi zer). All of these second-generation agents are currently undergoing phase I and II clinical testing in solid tumors and a variety of other cancers.

	Finally, given the unpredictable response to rapalog treatment, the development and validation of molecular biomarkers will be crucial in determining which patients will benefi t. Since 2000, major efforts have been directed toward achieving this end. A number of putative predictors have been identified in preclinical models, but are not yet fully validated in the clinic.

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Guertin DA, Sabatini DM. Defi ning the role of mTOR in cancer. 

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Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. 

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Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. 

The mammalian target of rapamycin (mTOR) is a master switch, central regulator, or key integrator of cell growth and proliferation

A Tale of 2 Complexes: The mTOR Signaling Pathway in Cancer Development

		The bond between bevacizumab and vascular endothelial growth factor.

	More than 1800 oncology specialists and other healthcare professionals turned out for the annual National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines & Quality Cancer Care conference, held in Hollywood, Florida, from March 9-13. Here are highlights on updates to the clinical practice guidelines:

	New Options for Metastatic Breast Cancer

	Eribulin (Halaven) has been added as a preferred single-agent option in the treatment of metastatic disease, while bevacizumab (Avastin), in combination with paclitaxel (Taxol), continues to be endorsed as treatment for patients with stage IV breast cancer. Denosumab (Xgeva) has been included in the guidelines as an additional option for the prevention of skeletal-related events.

	A footnote was added discouraging axillary lymph node dissection in certain women with early breast cancer and a minimal number of positive lymph nodes. And, with available study results deemed inconsistent, testing for CYP2D6 polymorphisms in order to determine the efficacy of tamoxifen is not recommended at this time.

	The second-generation tyrosine kinase inhibitors (TKIs) nilotinib (Tasigna) and dasatinib (Sprycel) are now recommended as first-line treatment for chronic myelogenous leukemia.

	In monitoring response to therapy, complete cytogenic response remains the gold standard; however, not achieving complete molecular response should not be considered as treatment failure.

		Photo shows in situ hybridization of labeled DNA, a known oncogene, that has been put into a mouse oocyte, where it paired with RNA (black dots in nucleus of immature cell).

	HPV Testing for Head and Neck Cancer Endorsed

	The guidelines now suggest that patients with oropharyngeal tumors be tested for the human papillomavirus (HPV). The guidelines also suggest that patients with hypopharyngeal cancer be evaluated and started on speech therapy as soon as possible to avoid severe speech impairment as the disease progresses.

	However, the issue of induction theory remains contentious, so the guidelines have not changed in that regard. The ongoing DeCIDE trial is expected to determine whether induction therapy is beneficial.

	Following the conference, the FDA approved ipilimumab (Yervoy) for the treatment of metastatic melanoma. On April 1, the NCCN added ipilimumab to the guidelines as a category 1 treatment option (ie, based on high-level evidence from randomized controlled trials) for patients with advanced or metastatic melanoma, although a footnote was added to warn of possible significant immunemediated complications.

	Mitotic index, the single most important predictor of survival, now replaces Clark level in defining clinical stage IB melanoma.

	The guidelines have been updated to note that routine imaging is no longer recommended for stage IIA melanoma patients with negative lymph nodes. Previous guidelines noted that this decision was left to the discretion of the clinician.

	A footnote was added to the section regarding the use of interferon alfa in the adjuvant treatment of stage III disease, indicating that the drug can be given as high-dose interferon for 1 year or peginterferon alfa-b for 5 years.

	Although there is no hard-and-fast rule about which patients should have one, physicians should discuss the possibility of sentinel lymph node biopsies with patients who have stage IB or stage II disease.

	The serum-free light chain assay and the fluorescence in situ hybridization for 1q21 amplification are now a recommended part of the initial diagnostic workup.

	The combination of bortezomib/cyclophosphamide/ dexamethasone has been added as primary induction therapy for transplant candidates. The bortezomib/dexamethasone combination and the melphalan/prednisone/lenalidomide combination have been included as therapy for primary induction for nontransplant candidates.

	The combinations of cyclophosphamide/bortezomib/ dexamethasone and cyclophosphamide/lenalidomide/ dexamethasone are now recommended for salvage therapy. The combinations of bortezomib/ dexamethasone and cyclophosphamide/thalidomide/ dexamethasone have been added to the guidelines as initial treatment for amyloidosis.

 NCCN executive vice president and chief operating officer

Are there plans to add any cancer centers to the existing 21 member institutions?

		No. While I think that virtually every comprehensive cancer center in this country has at one time or another asked for membership into NCCN, there is currently a moratorium on membership, and that has been the case for the last 2 years. We receive requests from cancer centers all across the world. Ultimately, we may consider some sort of international membership. But right now, there are no plans to add any cancer centers into the existing membership structure.

		The reasons for this are several-fold. All of our 21 member institutions pay very significant membership dues and are required to volunteer hours on many different committees. For example, last year the NCCN guidelines panel members from our 21 member institutions donated more than 16,800 hours of volunteer time—not including travel&mdash;just in the development and maintenance of the guidelines.

		Those cancer centers that have been with us since the beginning feel that NCCN has become very influential and prominent, and they don’t want to dilute the organization that they have worked very hard to build with their resources. Plus, the organization feels that, geographically speaking, most of the map is covered, so we would only consider additional members if we felt that they brought great value to NCCN as a whole.

	Role of CSF in Myeloid Growth Considered

	A revised footnote to the guidelines now states that there is a slight excess risk of acute myeloid leukemia and myelodysplastic syndromes in patients who have received colony-stimulating factors (CSFs) for chemotherapy-associated febrile neutropenia. In addition, the guidelines now recommend that primary prophylaxis with granulocyte CSF should be considered in patients who receive cabazitaxel chemotherapy for metastatic prostate cancer.

	Honing Approaches to Non-Hodgkin Lymphomas

	A new guideline has been added for post-transplant lymphoproliferative disorder; recommended treatment options include reduction of immunosuppression, single-agent rituximab (Rituxin), and chemoimmunotherapy.

	The combination of rituximab and bendamustine (Treanda) is now recommended as first-line therapy for follicular lymphoma. The updated guidelines also indicate that positron emission tomography scans might be useful in certain patients with grades 1 to 2 follicular lymphoma.

	The evaluation process for non—small cell lung cancer (NSCLC) now requires that the histologic subtype (ie, adenocarcinoma, large cell carcinoma, NSCLC not otherwise specified) be established before continuing with epidermal growth factor receptor (EGFR) testing. The testing is not recommended for squamous cell carcinoma, which has an incidence of EGFR mutations of >3.6%.

	A clarification states that erlotinib (Tarceva), recommended as fi rst-line systemic therapy in patients with 3 histologies (ie, adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified) and a positive EGFR mutation, should be for patients with a 0 to 4 performance status. The updated guidelines also include gefitinib (Iressa) as first-line therapy in these same patients.

	NSCLC patients should be tested for KRAS mutations, as these mutations are associated with tyrosine kinase inhibitor (TKI) resistance, thereby limiting the effectiveness of TKIs such as erlotinib and gefitinib. For patients not at high risk, the guidelines do not recommend routine lung screening tests with computed tomography until more data are accumulated.

	Dose-dense paclitaxel has been added as a category 1 option for first-line treatment of stage II, III, or IV epithelial ovarian cancer.

	Intraperitoneal (IP) chemotherapy should now be used in patients with stage III disease. Also, IP chemotherapy can be used in optimally debulked (ie, tumor ≤1 cm) stage II patients.

	The guidelines continue to recommend that borderline epithelial ovarian cancer with low malignant potential be managed primarily by surgery. For women who want to remain fertile, surgery limited to unilateral salpingo-oopherectomy is still recommended. For those whom fertility is not important, the guidelines continue to recommend standard ovarian cancer-debulking surgery.

	Bevacizumab (Avastin) is not yet recommended as upfront therapy with carboplatin/paclitaxel or as maintenance therapy.

	Although biomarkers continue to show promise in predicting future patterns of disease, the data on the utility of routine monitoring of CA-125 levels are inconclusive at this point. As a result, the guidelines encourage clinicians and patients to discuss the pros and cons associated with the routine monitoring of CA-125 levels.

	Active surveillance (ie, watchful waiting) was made more rigorous for men with low-risk prostate cancer.

	Sipuleucel-T (Provenge) has been added to the guidelines as an immunotherapy for asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. Symptomatic men, however, are not candidates for sipuleucel-T and should be considered for docetaxel/prednisone chemotherapy.

	Cabazitaxel (Jevtana) has also been added as a new second-line therapy for men with hormone-refractory metastatic prostate cancer who have failed docetaxel.

	As an alternative to zoledronic acid (Zometa), denosumab is now recommended for the prevention of skeletal-related events.

	A new observation pathway has been added to the resectable desmoid tumors section of the guidelines. Watchful waiting is less controversial with desmoid tumors because they do not metastasize as prostate cancer does. In addition, a new treatment pathway for these tumors has been added; it includes the options of surgery and/or radiation therapy and/or systemic therapy.

	The NCCN staging system for sarcomas now classifi es lymph node involvement as stage III, not stage IV.

	Molecular profi les and markers will become increasingly important to aid in the diagnosis, prognosis, and treatment of sarcomas.

Highlights on updates to the clinical practice guidelines from the annual National Comprehensive Cancer Network (NCCN) conference

Fine-Tuning Cancer Care: NCCN Changes 11 Guidelines

	Radiation therapy (RT) used in combination with androgen deprivation therapy (ADT) continues to be a viable strategy for treating patients with localized, high-risk prostate cancer but many clinicians are not employing it—even though guidelines suggest they should.

	Howard M. Sandler, MD, professor and chair of the Department of Radiation Oncology at Cedars- Sinai Medical Center in Los Angeles, California, made those points during the Interdisciplinary Prostate Cancer Congress held March 26 in New York City.

	Sandler cited an analysis that Cooperberg et al conducted based on the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (

	The researchers found the use of primary ADT for high-risk patients has risen to approximately 40%, while the use of external-beam RT declined to approximately 20%. High-risk patients, who comprise an estimated 15% to 25% of all prostate cancer patients, are most likely to die of the disease.

	“It is kind of shocking to me that when you go all across the country that’s what people are getting,” Sandler said. “Primary hormonal therapy really should be used sparingly in these patients. It’s not a trivial effect adding radiation to these patients. The magnitude of benefit is on the order of radical prostatectomy for localized prostate cancer.”

		Adapted from Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. 

Many clinicians are not employing radiation therapy used in combination with androgen deprivation therapy even though guidelines suggest they should

May 2011 | Oncology Live®