National Human Genome Research Institute Announces Genome Sequencing Centers

	for The Cancer Genome Atlas Pilot Project

he announcement of the fourth and final component of The Cancer Genome Atlas (TCGA) Pilot Project came on November 20, when the National Human Genome Research Institute (NHGRI) designated three leading research and cancer centers as TCGA Genome Sequencing Centers. The Genome Sequencing Centers (GSC) form one of four integrated components of the TCGA Pilot Project. The others, seven Cancer Genome Characterization Centers, the Data Coordinating Center, and the Biospecimen Core Resource were announced earlier. (see the last issue of 

 for more at http://www.nxtbook.com/nxtbooks/intellisphere/obn1106/.)

	The NHGRI and the National Cancer Institute announced that the three sequencing centers will devote a significant part of their DNA sequencing efforts to the TCGA project, strengthening the project’s endeavors to identify the genomic changes involved in three types of tumors: brain (glioblastoma), lung, and ovarian.

	The three GSCs are the Broad Institute of MIT and Harvard University, the Genome Sequencing Center at the Washington University School of Medicine in St. Louis, and the Human Genome Sequencing Center at Baylor College or Medicine. These research centers were selected from more than 20 organizations and institutes that have contributed to the Human Genome Project. For fiscal year 2007, the NHGRI has awarded these centers funds of $48 million, $41 million and $27.6 million respectively.

	The centers will be responsible for sequencing several genes and selected genomic targets that are identified by two separate approaches. The first will be “genes of interest” such as tumor repressors or oncogenes that are identified from scientific literature and by consultation with oncology experts. The other will be genes and genomic regions that the TCGA’s Cancer Genome Characterization Centers identify as candidates. To conduct these sequencing activities, the centers will receive quality-controlled samples of tumor specimens from the Human Cancer Biospecimen Core Resource.

	The GSCs are also expected to test and implement a number of new technologies to increase the speed and bring down the cost of DNA sequencing. The long-term goal is to sequence the entire genome of individual tumor samples.

	The centers “will play a pivotal role in our systematic effort to assess the range of genomic changes associated with malignancy,” said Mark Guyer, director of NHGRI’s Division of Extramural Research. “This genomic information will provide the research community with a powerful tool for uncovering new therapeutic targets and developing better strategies for diagnosing, treating and preventing cancer.”

	Visit the TCGA website’s page on Genome Sequencing Centers at http://cancergenome. nih.gov/components/gsc.asp.

                                                                                                                                                                                                      —Prachi Patel 

Several States and Washington, DC Taking Lead in Promoting Cervical Cancer Vaccination

ore than half a dozen states and Washington, DC have introduced legislation that would mandate middle-school age girls to receive a vaccine against the human papilloma virus (HPV), a known cause of cervical cancer. Some states have announced plans to make Merck’s Gardasil vaccine available at no cost—the full regimen of three shots over six months costs $360. Many states offer parents and guardians the choice to opt out of the requirement.

	In clinical trials on more than 11,000 girls and women worldwide, Gardasil has been shown to be 100% effective in preventing infection with HPV strains 16 and 18, which together cause about 70% of cervical cancer cases. It also protects against vaginal and vulvar cancers, which are linked to HPV, according to the American Society of Clinical Oncology. Gardasil received its first validation in July 2006 when the FDA approved the vaccine for sale to girls and women ages nine to 26. The CDC followed close on the heels of the FDA’s decision when its Advisory Committee on Immunization Practices recommended that girls ages 11 and 12 receive the vaccine. Then came yet another reinforcement, this time from the American Cancer Society, which published its guidelines for the vaccine in the January 19, 2007 issue of its journal 

	But even as proponents are commending efforts by US states as a critical step in the fight against cervical cancer, the initiative has drawn fire from critics. Groups who oppose government vaccine requirements as well as many social conservatives are saying that giving Gardasil to young girls could encourage sexual promiscuity. The issue is further complicated because of social and racial issues—a disproportionately high number of cases are found to occur in minority and low-income women.

	Whether or not the above states pass their respective bills, many health experts and advocates support the idea and see this as the right step towards combating the deadliest cancer to afflict women. According to the ACS, more than 11,000 women will be diagnosed with cervical cancer in 2007 and about a third of those women will die from the disease. The new vaccines,  combined with information about the viral causes of cervical cancer, “present and unprecedented opportunity for global cervical cancer prevention,” the ACS guidelines say.

	In the seven months since the FDA approved Gardasil sales, there has been a flurry of HPV vaccine-related legislative actions at the state level. Here is a recap of these actions:

	In December, the California Assembly Speaker introduced a bill that would require all girls in the state entering sixth grade to receive a HPV vaccine. The bill would allow girls to be exempted if their parents file a letter saying that participation is against their beliefs.

	A bill recently presented in the state legislature would require girls 12 and older to either show proof that they received Gardasil or that their parents have declined the immunization.

	The new year for Kentucky started with a newly introduced bill that would require girls in public and private middle schools to receive an HPV vaccination. Kentucky law states that immunizations are not required for “any child whose parents are opposed to medical immunization against disease and who object by a written sworn statement to the immunization of such child on religious grounds.”

	In early January, the state planned to begin distributing Gardasil to doctors as part of its plan to provide the vaccine at no cost to female minors between 11 and 18 years of age. The state health department estimates that about 17,000 girls will receive Gardasil over the year. Some doctors will offer the vaccine on a first-come, first-serve basis while others will use waiting lists.

	The state Governor announced on January 8 that the state will provide Gardasil at no cost to girls ages 11 to 18, making it the second state after New Hampshire to provide the vaccine for free. About 44,000 girls in the state are eligible for the vaccine, and the state had plans to distribute enough vaccines to physician offices and health department clinics by January 22. In the future, the state health department plans to focus on girls ages 11 and 12.

	On January 9, 2007, two DC city council members proposed a bill that would require girls entering the sixth grade to receive Gardasil. They would have to show proof of vaccination before enrolling in DC public schools, unless their parents or guardians opted out of the requirement. At 13.5 cases per 100,000 females, the cervical cancer rate in DC is much higher than the national average of 8.8. The Maryland senate and the Virginia General Assembly saw similar bills the week following the DC bill introduction.

	The state has the second highest cervical cancer mortality rate, after Washington, DC, with four women in 100,000 dying of the disease every year. On January 17, a state delegate announced that she would be introducing a bill that would mandate all girls to receive Gardasil by sixth grade. Georgia, New Jersey and Texas are now considering similar initiatives.

                                                                                                                                                                                                            —Prachi Patel 

Cervical Cancer Vaccine Sparks Scientific, Social Debate

Scientists and society disagree over routine HPV vaccination of girls and women

either leading cancer authorities nor the general public completely agree over whether and when girls and women should receive a new vaccine thought to prevent the most common forms of human papillomavirus (HPV). Left untreated, the sexually transmitted virus can develop, over time, into cervical cancer, considered one of the more preventable and curable of all cancers.

	The latest wrinkle in the vaccine debate came from the American Cancer Society, which recently said that, while it agrees with other cancer researchers that the vaccine is most effective when administered to girls as young as age nine, it does not agree the vaccine, Gardasil (quadrivalent human papillomavirus types 6, 11, 16, 18, recombinant vaccine) from Merck & Co., is effective in protecting women between the ages of 19 and 26 years old.

	“There are currently insufficient data to recommend for or against universal vaccination of females age 19 to 26 years in the general population,” according to the January/February 2007 issue of

. The ACS cited the article in their Jan. 19th position statement on the vaccine. “A decision about whether a woman age 19 to 26 years should receive the vaccine should be based on an informed discussion between the woman and her health care provider regarding

	her risk of previous HPV exposure and potential benefit from vaccination.”

	The ACS position is in conflict with several other recognized health authorities. The Food and Drug Administration approved the vaccine for use in girls and women ages nine through 26 years of age in early June. Later the same month, a US Centers for Disease Control Advisory Committee on Immunization Practices (ACIP) agreed with the FDA, saying women up to 26 years of age would still benefit from getting the vaccine. The Society of Gynecologic Oncologists concurred, supporting the ACIP’s recommendation for vaccinating women up to age 26, ideally before the onset of sexual activity. The American College of Obstetricians and Gynecologists also agreed with the ACIP recommendations.

	In addition to the scientific debate, there is societal debate over routine administration of the vaccine. Twenty-one states and the District of Columbia have reportedly already introduced legislation that would make the HPV vaccine mandatory for school-age girls, adding it to the list of other vaccines mandatory for school attendance. While most of these bills include a parental “opt-out” provision for the HPV vaccine, some parents resist the bill on principle. Several conservative religious groups, while supporting the availability of the vaccine for older women, say making the vaccine mandatory for school-aged children  undermines what they feel is the only way to avoid contracting HPV—abstinence. Some women’s health advocates say the vaccine may unintentionally cause women to skip routine PAP screenings, which they should continue to receive with or without the vaccine. Finally, the cost of the vaccine also concerns some groups. Gardasil must be administered three times over a six-month period at a cost of $120.00 per dose, which advocates for poor and uninsured women and children say puts it out of their reach.

                                                                                                                                                                                                           —Diane West

Cancer Deaths Drop, But So Do Mammography Screenings

t the same time they were cautiously celebrating a dramatic and historic drop in death rates from breast and other cancers in the United States, cancer researchers found themselves scratching their heads over the decline in the number of women  getting annual mammography screenings in recent years.

	The percentage of women over 40 who received an annual mammogram, considered a key component in detecting breast cancer in its earliest, treatable stages, dropped from 76.4 percent in 2000 to 74.6 percent in 2005, according to a US Centers for Disease Control report issued at the end of January. The data was gathered during a national telephone survey conducted from 2000 to 2005.

Articles

The Politics and Policy page provides a concise and timely round-up of key government-related oncology and biotechnology news. Content is focused upon the public sector activities that are most likely to impact the evolving oncology and biotech industries.

Politics & Policy: March 2007

%u25BA AMERICAN ASSOCIATION FOR CANCER RESEARCH

Novel Biomarkers May Make Early Detection in High-Risk Patients Possible, and Onconase May Have Potential as a Chemopreventive Agent

	Ranpirnase (Onconase®) may have potential as a chemopreventive agent, according to world-renowned malignant mesothelioma (MM) researcher Michele Carbone, MD, PhD, Professor and Director of the Thoracic Oncology Program and Clinical Professor of Pathology at the University of Hawaii’s Cancer Research Center of Hawaii and Chairman of the Alfacell Thoracic Advisory Board, who moderated a series of poster presentations at the annual meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007.

	Dr. Carbone highlighted the growing worldwide problem of asbestos exposure and its link to MM. He presented data showing that early detection in patients at high risk for developing MM is becoming more prevalent as a result of recently recognized biological markers, including soluble mesothelin-related protein (SMRP) and osteopontin (OPN).

	Dr. Carbone and his team of investigators evaluates whether these novel biomarkers could identify MM in its early stages in high-risk persons in Cappadocia, Turkey, where 50% of all deaths are caused by MM. Fresh sera were collected from 69 healthy persons ≥30 years of age, at 3 month intervals, and compared to sera from 11 individuals with a confirmed diagnosis of MM. A separate cohort of 12-year-old frozen sera from 72 apparently healthy villagers and 8 with known MM were also analyzed. Excellent discrimination for SMRP and OPN between healthy and MM was seen. For the 12-year-old sera, the SMRP and OPN sensitivity and specificity were preserved. The investigators concluded that SMRP and OPN are ex¬traordinarily promising markers for identifying early-stage MM in high-risk cohorts.

	Dr. Carbone also discussed the favorable toxicity profile and well-documented mechanism of action of Onconase, which directly affects the ubiquitin-proteasome proteolytic (UPP) pathway—the biomolecular pathway that has been shown to cause asbestos-related carcinogenesis. The elucidation of this pathway and future clinical testing may lead to the use of Onconase as a chemopreventive agent to potentially prevent the onset of MM, or reduce the doses of cytotoxic agents needed in patients who develop the disease.

	According to Dr. Carbone, “The potential of Onconase as an early, first-line preventative treatment for mesothelioma is an exciting development that we plan to investigate through clinical trials. With approximately more than 25 million asbestos exposure cases reported worldwide, we believe that Onconase might play a greater role in the treatment protocols for a much larger population than was originally envisioned for this dismal disease.”

	Onconase is a therapeutic product candidate based on Alfacell’s proprietary ribonuclease (RNase) technology. Onconase is a natural protein isolated from the leopard frog, and has been shown in preclinical models to target cancer cells while sparing normal cells. Onconase triggers apoptosis, the natural death of cells, via multiple molecular mechanisms of action.

Bavituximab Equivalent Generates Curative Immune Responses as Part of a Vaccine-Like Regimen in Preclinical Models of Aggressive Glioma

	The results of preclinical studies evaluating the antitumor responses to 2aG4—a mouse equivalent to the Peregrine Pharmaceuticals’ antiphosphatidylserine (anti-PS) antibody bavituximab&mdash;were presented at the annual meeting of the American Association for Cancer Research, Los Angeles, CA.

	Anionic phospholipids, primarily PS, become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. Dr. Jin He and colleagues at the University of Texas Southwestern Medical Center, Dallas, TX explored the possibility of enhancing the immunogenicity of irradiated glioma cells by treating them with 2aG4 in vitro.

	In previous research, Dr. He and colleagues treated rats with orthotopic glioblastoma with single-fractionated radiation combined with 2aG4. The treatment resulted in a marked prolongation of survival time and some tumor cures (15%). Surviving animals were immune to intracerebral challenge with live, untreated F98 glioma cells. These findings suggested that PS on tumor cells might be suppressing the host immune response to the tumor cells and that blocking PS with 2aG4 restored immunogenicity.

	In the current study, Dr. He and his team evaluated the possibility of enhancing the immunogenicity of irradiated F98 glioma cells by treating them with 2aG4 in vitro. A 57% long-term survival rate was observed in the 2aG4 group, versus a rate of 16% for rats immunized in the control antibody group. The superior survival in the 2aG4 group was statistically significant (

 <  0.01). In addition, the antibody-coated F98 glioma cells were able to elicit specific T-cell responses, based on enhanced production of tumor-reactive interferon-gamma (IFN-γ)—producing T cells and increased cytotoxicity of T cells on F98 gliomas. The investigators concluded that anti-PS antibody treatment of tumor cells may enhance cross-presentation of tumor antigens as well as the generation of glioma-specific T cells by dendritic cells. Anti-PS antibody treatment might therefore be combined with radiosurgery in clinical settings to treat brain tumor patients.

	The key role of the bavituximab equivalent’s anti-PS activity in protecting these animals was illustrated by the fact that a group receiving irradiated control antibodies that did not block PS only achieved a 16% long- term survival rate. These data may have profound clinical significance because the glioma cells used in the study are a highly aggressive variety, and a 2aG4 vaccine-like regimen resulted in a strong immune response to the cancer, which was not seen in the controls.

	Steven W. King, President and CEO of Peregrine, remarked, “These exciting data suggest a potential new application for bavituximab and our anti-PS antibody platform as part of a cancer vaccine regimen that aims to restore the ability of the patient’s own immune system to recognize and fight cancer. Based on these promising results, we are continuing our evaluation of these vaccine-like regimens containing bavituximab for potential application to a variety of cancers.”

	Bavituximab is a targeted monoclonal antibody that binds to a PS, which is normally located on the inside of cells, but which becomes exposed on the outside of the cells that line the blood vessels of tumors. Once bound to tumor blood vessels, bavituximab alerts the body’s immune system to attack the blood supply of the tumor, thereby resulting in tumor-cell death. PS blockers may have the potential to help reverse this suppression and enable the immune system to attack the cancer more effectively. As an anticancer immunotherapeutic agent, bavituximab may have broad potential in a wide variety of solid cancers. It is currently in Phase Ia cancer safety trials as monotherapy and in a Phase Ib trial in combination with docetaxel and other chemotherapy agents in patients with advanced solid cancers, including carcinoma of the prostate, breast, and lung.

Survey: Biotech-Based Disease Cures “A Top National Issue”

General Public and Biotech Leaders View Curing Disease More Urgent than Terrorism, Immigration Issues

	National security concerns, including terrorism and illegal immigration, take a back seat when it comes to finding cures for cancer and other serious diseases, according to a recent nationwide survey of public citizens and leaders in the biotech industry.

	The findings were announced at the May 2007 BIO International Convention held in Boston this year.

	According to the survey, conducted by the Public Opinion Strategies and Peter D. Hart Research Associates groups, 78% of 800 registered U.S. voters who participated in a telephone poll this spring considered finding cures for serious diseases such as cancer, Parkinson’s, Alzheimer’s, HIV/AIDS and MS a “top national issue.” Concern over this issue was tied with improving public education, followed closely by improving the economy and job creation (77%). Defending the country against terrorism and stemming illegal immigration came in fourth at 71%. The survey had a margin of error of 3.5%.

	“The results of this poll show strong public support for our industry,” according to Biotechnology Industry Organization president Jim Greenwood. The survey results, he added, were consistent with the 2007 meeting’s theme: “New Ideas. Bold Ventures. Global Benefits.”

	Oncology-related patient and health advocacy groups represented at the Convention included the American Association for Cancer Research, The Leukemia & Lymphoma Society, the National Breast Cancer Coalition Fund and the Prostate Health Education Network.

Understanding of Biotech, Cost of Access Impacts Public Opinion

	Only 45% of public survey participants initially said they viewed the field of biotechnology “favorably”, but this figure shot up to 86% when participants were told biotechnology had the potential to extend the quality of life for patients with serious disease like cancer. Additionally, 80% of the public survey respondents said full access to biologically—engineered medicines should be extended to Medicare and Medicaid patients. Fourteen percent viewed the increased cost to the government of providing this kind of universal access to advanced treatments as “troubling.” (Notably, 54% of the public respondents were male and earning more than $100K per year).

Biotech Leaders Interested in Curing Disease, Keeping Government Regs Out

	Much like the public survey participants, some 2,000 biotech professionals surveyed indicated a strong interest in finding cures for serious diseases, with 94% saying they were optimistic about finding cures for many within the next two decades. However, a majority of biotech leaders think “regulatory burdens” (i.e., government oversight) would impede their progress, with 71% indicating they want government to stay out of innovation whenever possible, including such controversial topics as stem cell research. Still, 59% of industry leaders said they want increased federal funding for biomedical research.

	The four-day 2007 BIO International Convention drew over 22,000 attendees from almost all states in the U.S. and 64 countries worldwide; one-third conference attendees hailed from outside of the U.S. Attendance was up almost 15% from the previous year and included keynote speakers such as actor Michael J. Fox, who founded the Michael J. Fox Foundation for Parkinson’s Research several years after being diagnosed with the condition himself, and Queen Noor of Jordan, whose husband, King Al-Hussein of Jordan, died in 1998 after a battle with non-Hodgkin’s lymphoma.

Biotech Leader Calls Patient, Industry Support The “Only Way” To Combat Cancer

President of BIO says government must support research without overly zealous regulation of the industry if cancer cures are to be discovered

	The head of an industry organization representing over 1,000 biotechnology companies, academic institutions, and other affiliates worldwide says patients, scientists, and industry must support a political environment conducive to drug discovery if diseases like cancer are to be beaten.

	“Continued innovation is the only way to make progress against cancer,” James C. Greenwood, president and CEO of the Biotechnology Industry Association told 

. “Physicians, biomedical innovators and patients need to advocate for a regulatory environment that supports innovation through strong intellectual property protection, access to investment capital and fair pricing to enable innovators to recover development costs and invest in new research.”

	Mr. Greenwood’s comments come as the fight for the presidency of the United States in 2008 is well underway, with topics such as stem-cell research and vaccines against sexually transmitted cancers often making their way into debates among candidates.

	A regulatory environment which both invests in discovery while not imposing heavy regulation of the industry will, Mr. Greenwood says, lead to ground-breaking cancer cures. “Emerging advances will soon enable us to place nanoparticles inside tumors to image and attack tumors,” he says. Additionally, he says “advances in gene therapy will enable scientists to ‘switch off’ cancer cells, and “nanosensors will enable us to simultaneously test for hundreds or even thousands of different biomolecules in a drop of blood.”

	The record-breaking turnout and panel discussions at May’s BIO 2007 meeting, Mr. Greenwood says, “demonstrated that biotechnology innovation continues to completely reinvent cancer prevention, detection and treatment, moving us ever closer to our vision of making cancer obsolete.”

This issue features reports from:  American Association for Cancer Research meeting April 14-18, 2007 Los Angeles, CA  BIO International Convention May 6-9, 2007 Boston, MA

The Rapid Reporter: June 2007

%u25BA Supplemental Drug Application Submitted for Postoperative Nausea and Vomiting

MGI Pharma and Helsinn announce submission for Aloxi® injection for use in postoperative nausea and vomiting

	MGI Pharma Inc., a biopharmaceutical company focused in oncology and acute care, and its partner Helsinn Healthcare SA, a privately owned Swiss pharmaceutical group, have announced that a supplemental New Drug Application (sNDA) for Aloxi® (palo¬nosetron hydrochloride) Injection for the prevention of postoperative nausea and vomiting has been submitted to the U.S. Food and Drug Administration (FDA).

	Aloxi is a selective serotonin subtype 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor. 5-HT3 receptors are located on the nerve terminals of the vagus nerve in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferent nerves to initiate the vomiting reflex. Currently, Aloxi is indicated for: (1) the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy; and (2) the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

	According to Lonnie Moulder, President and Chief Executive Officer of MGI Pharma, “Postoperative nausea and vomiting affects approximately one-third of patients who undergo surgery, and can lead to increased health care costs resulting from delayed discharge from hospitals or ambulatory surgical centers, and hospital re-admissions. Studies have demonstrated an ongoing need for effective long-term agents that can improve the control of both nausea and vomiting post-surgery. The unique pharmacodynamic profile and extended duration of activity of Aloxi may prevent postoperative nausea and vomiting for up to three days with a single dose. We believe this submission is an important step in maximizing the potential of Aloxi.”

	The sNDA submission is based on favorable results from two multicenter, randomized, placebo-controlled, Phase III trials conducted to evaluate the safety and efficacy of three doses of Aloxi. In these trials, a total of 1,219 patients undergoing elective outpatient abdominal or gynecological laparoscopic surgery (Study PALO-04-06) or elective inpatient gynecological or breast surgery (Study PALO-04-07) were randomized to receive one of three single intravenous doses of Aloxi or placebo prior to administration of anesthesia. Both clinical trials successfully met the primary efficacy endpoint of complete response, defined as no emesis or use of rescue medication, for the 24-hour time period following surgery, for the selected dose of 0.075 mg. In addition, both trials achieved the secondary endpoints of complete response for the 48- and 72-hour postoperative time periods.

	Postoperative nausea and vomiting occurs commonly and affects more than one-third of patients undergoing ambulatory and in-patient surgical procedures. In the United States approximately 30 million doses of 5-HT3 receptor antagonists are used annually for the management of postoperative nausea and vomiting. The primary factors that can increase the risk for postoperative nausea and vomiting include female gender, non-smoking status, prior history of postoperative nausea and vomiting or motion sickness, length of surgery, and use of volatile anesthetics and opioids. If not prevented, postoperative nausea and vomiting may result in delayed discharge, hospital re-admission, and increased healthcare costs.

%u25BA Medicare Proposes Limits on Coverage for Erythropoiesis-Stimulating Drugs

Medicare has proposed limiting coverage for the erythropoiesis-stimulating agents Epogen® (epoetin alfa, Amgen), Aranesp® (darbepoetin alfa, Amgen), and Procrit® (epoetin alfa, Johnson & Johnson)—drugs that accounted for more than $10 billion in sales last year&mdash;amid renewed concerns over safety, including thrombosis, cardiovascular events, tumor progression, and reduced survival. The erythropoiesis-stimulating drugs have been under scrutiny in recent months after studies showed mixed results when used in cancer patients not receiving chemotherapy.

	The Centers for Medicare and Medicaid Services (CMS) said in a statement that the drugs were “not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the erythropoiesis-stimulating agents on their underlying disease, or because the underlying disease increases their risk of adverse effects related to erythropoiesis-stimulating agent use.”

	“We pay close attention to U.S. Food and Drug Administration (FDA) black-box warnings because the safety of our Medicare beneficiaries is paramount,” stated CMS Acting Administrator Leslie Norwalk. “We have carefully examined the evidence surrounding these labeling changes and have issued this proposed decision to protect our beneficiaries.”

	Medicare spends more on the anemia medications, which are taken by more than 1 million people each year, than on any other drug. The agency started its review after the FDA added a “black-box warning” to the drugs in March, advising doctors to prescribe them at their lowest possible doses and only to approved patients.

	The FDA approved the drugs more than a decade ago for the treatment of anemia caused by chemotherapy in an array of cancer patients and for patients with kidney failure. However, physicians have prescribed the drugs for a wide variety of other patients, including those not on chemotherapy, and in greater dosages than those recommended by the FDA. In its proposal to limit coverage, Medicare said it would no longer pay for cancer patients’ use of the drugs if their anemia wasn’t related to chemotherapy or if the drugs were prescribed to prevent chemotherapy-related anemia.

	CMS said it would accept public com¬ments until June 13 before making a final decision on the coverage proposal, which is posted at 

www.cms.hhs.gov/mcd/view-draftdecisionmemo.asp?id=203

	The possibility of Medicare cuts for the anemia drugs is a potential watershed event, possibly opening the door to significant downstream private-payer pressure. The ramifications on earnings for Amgen and Johnson & Johnson are even more likely. If the cuts are actually made, it is hoped that appropriate use of the erythropoiesis-stimulating agents in the cancer setting would not be diminished.

%u25BA Femara Reducses Risk of Early Breast Cancer Relapse in Postmenopausal Women

Study shows a reduction in the risk of cancer spreading to the lungs, the brain, or the bones

	A new analysis of the aromatase inhibitor Femara® (letrozole) shows that the drug reduces the risk of early breast cancer spreading to distant parts of the body such as the lungs, the brain, or the bones in postmenopausal women. Such distant metastases make it extremely likely that a patient will succumb to the disease.

	Femara, made by Switzerland-based Novartis, is the only aromatase inhibitor to be approved in the U.S. for adjuvant therapy, extended adjuvant therapy, and advanced breast cancer.

	The new analysis reveals that after two years of post-surgical therapy, postmenopausal women with hormone-sensitive early breast cancer who are treated with Femara experienced 30% fewer early breast cancer recurrences at distant sites compared to women who were treated with tamoxifen. They study was published in the May issue of 

	In the retrospective analysis, researchers at independent cancer research centers around the world looked at data from more than 7,700 women who were treated in the BIG 1-98 trial. The trial was conducted by the International Breast Cancer Study Group to do a head-to-head comparison of Femara and tamoxifen, and was supported by Novartis. The researchers found that at a median follow-up of two years, approximately three-quarters of early cancer recurrences occurred at distant sites such as bones of vital organs. However, they found that there were 30% fewer distant metastases in the Femara group as compared to the tamoxifen group. Femara also showed a significant reduction in the recurrence risk at the same breast, the other breast, and the lymph nodes.

	The results showed that patients with the highest risk of early recurrence had tumors larger than five centimeters, four or more positive nodes, positive estrogen receptor status but negative progesterone status, grade three tumors, and invasive disease. Notably, women with node positive disease, who are considered to be at a higher risk of recurrence, maintained a lower risk of relapse when treated with upfront Femara than with tamoxifen.

	“These results provide the tip of the iceberg and for the bigger picture,” said Hugh O’Dowd, Business Unit Director at Novartis Oncology UK. “Physicians will be eagerly awaiting the results of the BIG 1-98 sequencing arms, which hope to indicate the optimal strategy for using Femara post surgery and are due to be ready for 2008.”

%u25BA Researchers Develop Pancreatic Cancer Risk Model

     Will help physicians with early screening decisions

	Inherited genes lead to about 10% of aggressive and highly fatal cases of pancreatic cancer. But with a new software model, people with a family history of pancreatic cancer have a way to accurately predict their chance of inheriting a gene for the disease and their lifetime risk of developing the disease. The model, developed by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, MD, is designed to help genetic counselors and physicians decide who would benefit most from early screening.

	Pancreatic cancer strikes more than 37,000 people in the U.S. every year, and it kills about the same number. The disease is often not detected before it has metastasized and the prognosis is dismal, with the five-year survival rate at less than 5%. “Therefore, the only way to fight this disease is through early detection, and individuals at high-risk due to their family history represent a group that will benefit from early detection,” Alison Klein, PhD, assistant professor at Johns Hopkins who led the new model’s development told 

	The risk calculator tool, called PancPRO, is very similar to the ones Johns Hopkins researchers have developed to predict familial breast and colon cancer risk, which should make it easy for physicians familiar with those models to use the new one, Dr. Klein said. “It is quite easy to compute risk,” she said. “A physician would need to obtain information on the current age or age at death and pancreatic cancer status for each relative of the patient being counseled. This information is then entered into user-friendly software.” The software evaluates a percentage probability score that a person carries a pancreatic cancer gene and also calculates an individual’s risk of developing the disease in his or her lifetime. Researchers have not yet identified specific genes that cause pancreatic cancer, but they can estimate high disease risk based on clusters of family members who have a history of the disease.

	Dr. Klein and her colleagues tested the software by feeding in family history data given by more than 6,000 individuals in 961 families who were in the Hopkins pancreatic cancer registry. The researchers divided the registrants into groups representing the number of pancreatic cancer patients in each family. Then they compared their model’s predictions with actual disease occurrences in the families up to 100 years later. They found that PancPRO accurately estimates risk 75% of the time. By contrast, current methods for calculating the disease risk are accurate 61% of the time.

%u25BA Beyond BCG: New Bladder Cancer Treatments Offer Hope of Tailored, More Effective Therapies

Identifying the expression of certain proteins by bladder tumors may point the way to more targeted therapies

	    beyond the traditional “gold standard” of care

Leading cancer centers such as Memorial Sloan-Kettering in New York are participating in a number of investigational trials with the goal of creating more “tailored” bladder cancer treatments, from identifying high-risk patients by certain genetic markers in tumors to combining chemotherapy drugs that are already successful in treating other types of cancers.

	The traditional course of treatment of superficial bladder cancer (tumors which have not invaded the muscle surrounding the bladder) has been surgical removal and periodic monitoring. Patients deemed to be at higher risk of recurrence are also often given Bacillus Calmette-Guerin (BCG) therapy following tumor removal. BCG, inactivated tuberculosis bacteria, is introduced directly into the bladder to produce an inflammatory response which hinders the reurn of tumors in many, but not all, bladder cancer patients.

	Newer, genetically-based courses of treatment currently being investigated include identifying those patients most at risk for recurrence by the presence of a certain protein, p53, which monitors DNA changes in cells. Higher p53 levels can indicate the presence of a more aggressive form of bladder cancer and warrant early removal of the bladder. Another genetically based therapy being investigated at Memorial Sloan Kettering includes the study of retinoblastoma genes and those that affect programmed cell death, including bax,bcl-2, and mdm-2. Disturbances in the function of these genes may be markers for aggressive forms of bladder cancer or help locate sites where the cancer is at risk for metastising.

	Other treatments that have shown early promise include a new proprietary mycobacterial cell wall-DNA complex (MCC) trademarked under the name Urocidin by Belleville, Ontario-based Bioniche. Early data, according to the company, show MCC’s mechanism of action kills non-invasive bladder cancer cells directly while helping to stimulate the body’s own immune system response. Urocidin was granted fast-track status by the FDA. Clinical trials comparing the efficacy of Urocidin as a first-line therapy in non-invasive bladder cancer to traditional BCG therapy are expected to commence at Memorial Sloan Kettering and other cancer centers within the next few months.

	Oncologists are also looking at drugs currently used in the treatment of other types of cancer for potential use in bladder cancer patients. One Phase II trial is looking at whether the addition of bevacizumab, a drug currently used to treat advanced colon cancer, can boost the effectiveness of gemcitabine and carboplatin, a combination chemotherapy treatment used in the treatment of advanced bladder cancer by interrupting tumor angiogenesis. And an oral chemotherapeuticl drug currently used to treat kidney cancer, Sunitinib (sutent A) is being studied for its effectivness against metastatic bladder cancer.

	Word of the new therapies was welcome news to attendees at a recent bladder sup¬port group for patients and their caregivers held at Memorial Sloan-Kettering’s Sidney Kimmel Center for Prostate and Urologic Cancers, many of whom wondered aloud why standard bladder cancer treatments hadn’t progressed beyond BCG for some time compared to the advances in the treatment of other cancers. Bladder cancer is diagnosed in 38,000 men and 15,000 women in the U.S. each year, according to the National Cancer Institute, and is the fourth most common cancer in men and the eighth most common in women. Risk factors are hard to pin down, although the cancer rarely occurs in people under 40 years old and seems more prevalent in smokers.

%u25BA Doctor’s Own Brush With Bladder Cancer Gives Him Uniqe Insight to Patients’ Challenges

Geriatrician’s experience heightens his awareness of he quality-of-life issues patients face during bladder cancer

Like many proud parents in this time of year, Dr. Monte Peterson talks proudly about the upcoming graduation of his son from New York’s Syracuse University. “He started off in journalism,” the tall, soft-spoken doctor says, “but decided to go into graphic design instead.” Another son is at John Hopkins University studying chemistry. “They couldn’t be more different,” he smiles, “and my wife and I are very proud of both of them.”

	Dr. Peterson, a devoted geriatrician at St. Vincent’s Hospital in New York, says he has always had an affinity for older people. “I grew up on a farm in Iowa in a town predominately made up of people of Swedish decent, and I can tell you Swedes are among the longest-living people in the world,” he says. “My parents were around 40 years old when I was born, and I was very close to my maternal grandmother, so I became very interested in geriatric care and primary care of older adults at a young age.”

	Because of the age of the patients he sees—many are in their mid 80’s and 90’s&mdash;Dr. Peterson has been involved in the care plan of bladder cancer several times. But he never thought he would one day be sharing the same battle.

	He says it started with the usual signs earlier this year—frequent and painful urination&mdash;which the doctor initially chalked up to prostatitis, not an unusual occurrence for a man of his age. “I wasn’t thinking it was bladder cancer,” he says, “because I’m only 54 and I’ve never smoked. It’s much more common in older people, so it wasn’t a diagnosis at the top of my list.” Nonetheless, Dr. Peterson trusted his colleagues judgment as he underwent more and more diagnostic tests.

	“That was the first thing I took away from the experience,” he says. “I’m definitely more sensitive to how difficult it is to wait for the results of tests, no matter what they are.”

	Unfortunately, in Dr. Peterson’s case, the tests ultimately proved positive for bladder cancer.

	Acknowledging the old adage that doctors can be some of the 'worst’ patients, Dr. Peterson decided not to involve his colleagues in the continuance of his care, a decision he says they ‘graciously’ understood. Instead, he went to Dr. Harry Herr at Memorial Sloan-Kettering Cancer Center. There, it was determined his best course of treatment would be having the transurethral resection of the bladder tumor (TURBT) followed by a course of BCG treatment. After his TURBT, Dr. Peterson was sent home with a Foley catheter overnight.

	“I have to tell you, it was pretty uncomfortable,” he says, “so now I know what that’s like. Especially standing up—I was seeing stars. I made it through the night, but I took it out myself the next morning after checking with staff from the hospital.” Dr. Peterson says the pain and discomfort of the catheter was among the strongest experiences he gained. While he had always urged his interns and residents to avoid inserting catheters in elderly patients if there were any alternative, he urges them to do so even more.

	He also said he tells patients to take it easy when recovering from procedures. “I tried to go back to work the day after my first rigid cystoscopy and learned that my need to go to the bathroom every 15 to 20 minutes wasn’t going to let me make it on the subway, let alone be conducive to seeing patients,” he says.

	Like any other patient, Dr. Peterson said he read everything he could about his condition as well as some inspirational reading to keep him positive. It’s been two weeks since he finished his last BCG treatment, and so far, so good.

The articles featured in this issue are:  1) Supplemental Drug Application Submitted for Postoperative Nausea    and Vomiting by John D. Zoidis, MD 2) Medicare Proposes Limits on Coverage for     Erythropoiesis-Stimulating Drugs by John D. Zoidis, MD 3) Femara Reduces Risk of Early Breast Cancer Relapse in      Postmenopausal Women, and more

News Reports: June 2007

 American Association for Cancer Research (AACR) Annual Meeting in Washington, DC, in April, Pfizer presented a broad overview of its current oncology pipeline. This includes investigating new indications for approved drugs like sunitinib (Sutent) and novel agents like axitinib and crizotinib. Pfizer said it has 31 oncology drugs in the pipeline, and Jamie Christensen, MD, director of Translational Research at the company, said he expects several to come to market in the next 3 to 5 years.

Of the 31 oncology drugs Pfizer has in the pipeline, Christensen said “Over half have shown a viable strategy by molecular model or have shown response in certain patient populations.” With Pfizer expecting several of these compounds to make it to market in the relatively near future, the company said it intends to maximize their potential with premarket development and support at launch.

Sunitinib Being Explored in Other Cancers 

A day after the close of the AACR meeting, Pfizer announced that it was discontinuing the SUN 1170 phase III open-label study of sunitinib malate (Sutent) in advanced hepatocellular carcinoma (HCC). The trial was discontinued after a review by the independent Data Safety Monitoring Board (DSMB) confirmed “a higher incidence of serious adverse events in the sunitinib arm compared to the sorafenib [Nexavar] arm,” Pfizer said in a press release. In addition, the committee said sunitinib demonstrated neither superiority nor noninferiority to sorafenib in patients with advanced HCC. Sorafenib, manufactured by Onyx Pharmaceuticals and Bayer, is currently the only oral treatment known to extend life for people with HCC. 

“The disappointing outcome of this trial challenges all of us to work harder to understand the complex biology of this disease,” said Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs for Pfizer’s Oncology Business Unit, in a statement issued by the company. Despite this setback for sunitinib in HCC, Pfizer views the drug as one of its most promising. 

The FDA has already approved sunitinib as a treatment for metastatic renal cell carcinoma (RCC) and in gastrointestinal stromal tumors (GISTs) that are refractory to imatinib mesylate (Gleevec) or in patients with GIST who demonstrate intolerance to imatinib. “The result of this trial in HCC patients does not diminish our confidence in Sutent for the treatment of patients with RCC and GIST,” Rothenberg said. 

Sunitinib, a tyrosine kinase inhibitor, works by blocking multiple molecular targets implicated in the growth, proliferation, and spread of cancer 

endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)—are angiogenic cytokines thought to play important roles in the development and progression of several tumors. Christensen said Pfizer plans to continue exploring applications for sunitinib in other cancers. “We’ve hit a few recent bumps in the road,” he said, “but we are taking these as learning experiences.” Sunitinib is being investigated in non—small cell lung cancer (NSCLC), advanced castration-resistant prostate cancer, and as an adjuvant therapy in RCC. Data from an ongoing trial of sunitinib in NSCLC are expected later this year.

cells. Two important targets of sunitinib—vascular 

Pfizer has several promising new agents in the works, including axitinib, another inhibitor of VEGFR and PDGFR. Earlier trials of axitinib in patients with advanced RCC have shown the drug to be highly active, and experts are anticipating phase III trial results, which should be available later this year. Pfizer was forced last year to close a phase III trial comparing axitinib with gemcitabine versus gemcitabine alone in this patient population after the DSMB found no evidence that the combination would improve survival compared with standard care. Axitinib is also being studied in phase II trials for lung, gastrointestinal, thyroid, and breast cancer. 

Crizotinib is another agent in Pfizer’s pipeline that has generated a lot of excitement as a potential treatment for NSCLC. Crizotinib is a first-in-class novel therapeutic that inhibits the anaplastic lymphoma kinase (ALK), thought to be a key driver of lung tumor growth in the 4% to 7% of patients with ALK-positive tumors. “In some cases, you can even eyeball the veno-differences in the ALK gene,” Christensen said. In addition, crizotinib potentially inhibits the pathways that contribute to the proliferation of c-mesenchymal-epithelial transition factor, or c-MET, a protein overexpressed in some tumors. Although trials are only in phase I/II, Christiansen said he is encouraged by the early results. Of 50 young patients with NSCLC in early trials, crizotinib showed clinical benefit in 64% of patients and 90% experienced slower disease progression. Pfizer will be presenting data on these studies in a plenary session at the American Society of Clinical Oncology (ASCO) annual meeting in June. While this is only a small subset of patients with NSCLC, the level of response suggests that crizotinib might turn out to be a very important drug for these patients (see West’s Points on page 18).

Pfizer has two dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in early trial development. Cellular signaling along the PI3K pathway regulates the cell cycle and apoptosis. Mutational activation of the PI3Ka gene, PTEN loss of function, or activation of receptor tyrosine kinases, such as EGFR and HER2, interaction with activated Ras, or PIKC3A mutations contribute to elevated activity along the PI3K pathway. Aberrant PI3K/Akt/mTOR signaling has been implicated in several types of solid tumors and lymphomas. 

Pfizer presented preclinical data from several studies on these investigational agents at the recent AACR meeting. PF-04691502, which is administered orally, has demonstrated “potent and selective activity in in vitro biochemical, cell, and xenograft models,” according to study investigators. Early data suggest it has broad activity in a range of cancers, including ovarian cancer and glioblastoma. In NSCLC xenograft models, PF-04691502 inhibited tumor growth, including in a line of NSCLC resistant to erlotinib (Tarceva).

PKI-587/PF-05212384 is administered intravenously, and it was found to inhibit tumor cell survival and proliferation in vitro. In xenograft models of human breast, glioma, and lung cancer lines, investigators said it demonstrated “compelling efficacy.”

Pfizer’s focus on newly identified targets, such as ALK and the PI3K pathway, has resulted in what are potentially important innovations in cancer treatment. In explaining the rationale behind Pfizer’s approach to research and development in oncology, Christensen said, “We are trying to study the mechanisms of resistance and the molecular defects in people who progress in certain cancers.” 

Other drugs in development in Pfizer’s oncology division include two pan-HER/erbB targeted agents in phase III trials; we reported data for one of these agents, Neratinib, in the March issue. Neratinib is being investigated for metastatic breast cancer. Pfizer is also conducting studies of compounds for hematologic malignancies, including a phase III trial of bosutinib in chronic myelogenous leukemia. Data on this trial should be available later in the year.

Even before complete data are available, some in the scientific community are hailing Pfizer’s efforts as a potential harbinger of a new era in cancer treatment. “This does not mean that we will cure all diseases,” said Tyler Jacks, PhD, president of AACR and director of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. “But cancer patients will experience significantly longer survival, including those with the most devastating diagnosis, as we implement the new approaches we’re discovering today.” 

At the 101st American Association for Cancer Research (AACR) Annual Meeting in Washington, DC, in April, Pfizer presented a broad overview of its current oncology pipeline.

Pfizer's Innovative Oncology Division Is Right on Target

It has been 15 years since researchers discovered that mutations in the BRAC1 and BRAC2 genes predispose some women to certain breast and ovarian cancers and 10 years since trastuzumab (Herceptin) became a cornerstone of treatment for women with HER2-positive breast cancer.

Such discoveries paved the way for more scientifically advanced approaches to breast cancer; whereas, oncologists once selected a treatment based on clinical presentation and hoped for the best, these days they can often tailor treatment to a patient’s particular circumstances. This has transformed the diagnosis of breast cancer from a sentence of early death or disfigurement to a disease that, although serious, is often manageable with the appropriate treatment.

While researchers have supplied more answers, they have also generated more questions as their attempts to fine-tune the diagnosis and treatment of breast cancers have uncovered new complexities about the nature of this disease, including the discovery of breast cancers that are resistant to multiple receptor-targeted treatments.

Triple-negative breast cancer: Biology, pathology, and therapy

Researchers were elated when HER2-positive breast cancer was first identified. The discovery allowed them to develop drugs that targeted and disabled the receptors in women whose tumors were HER2-positive. Down the line, however, they found that some tumors were resistant not only to HER2 but also to progesterone receptors (PRs) and estrogen receptors (ERs). These tumors are referred to as triple-negative breast cancer because they are HER2-negative, PR-negative, and ER-negative.

About 15% of women with breast cancer in the United States have triple-negative tumors, according to Dan Silver, MD, of the Dana-Farber Cancer Institute at Harvard Medical School, who is studying the biological underpinnings of this condition. Triple-negative breast cancer primarily occurs in younger women, 70% of whom have BRAC1 genetic mutation, and it is more prevalent in black women than in white women. Dr. Silver says that, unfortunately, patients with triple-negative breast cancer have a poor prognosis. Although triplenegative breast tumors tend to be less aggressive than ones that test positive for one of the 3 growth receptors, they present their own challenges. If the cancer does not have a growth hormone receptor to target in an effort to disrupt tumor-cell growth, what course of treatment should be pursued?

Some researchers have begun to focus their efforts on turning these ‘negatives’ into a positive for such patients, reexamining older chemotherapies and hunting for new drugs that target other receptors known to contribute to tumor growth in triple-negative breast cancer. Most clinical discoveries are still in the preliminary stages of investigation and are not quite ready for prime time, but they do offer a glimpse into the future of treatment for patients who have triple-negative breast disease.

Identifying cell lines and molecular markers in triple-negative breast cancer tumors

Dr. Silver and several of his colleagues believe that cell lines exist that could be used to identify women with triple-negative disease. Consensus on what these cell lines are and how to detect them remains elusive. “Oncologists are still rather in the dark in terms of sporadic triple-negative disease,” said Dr. Silver. “But we know most of them fall into the BRAC1 subtype.” Dr. Silver says it would be ideal if researchers found a way for physicians to determine the tumor’s specific cell line in patients with triple-negative cancer before they select a course of treatment.

Cisplatin may be one treatment option for women with triple-negative disease, regardless of whether they have the BRAC1 gene mutation. One clinical trial examined tumor response to neoadjuvant cisplatin in 23 women with stage II/III triple-negative breast cancer. The study found that 14 had either a “complete” or “significant” response to cisplatin therapy. A smaller trial involving 10 women with a BRAC1 mutation found that 9 showed complete pathologic response to cisplatin therapy.

Dr. Silver said that if these early observations are borne out, “it appears that a subset of sporadic triple-negative breast cancer will share the susceptibility to cisplatinum shown by the BRCA1-related breast cancers.” He said these early clinical observations are consistent with findings from preliminary laboratory models that show BRCA1 and triple-negative tumors demonstrate mitomycin C and poly (ADP-ribose) polymerase (PARP)—inhibitor sensitivity (PARP is a key enzyme in DNA repair). Dr. Silver cautioned “don’t try this at home,” emphasizing the preliminary nature of these findings. “These data are from preclinical models and are very small; there are many ways in which they could be wrong or misleading. These considerations, and others like them, should be used to think creatively about future clinical trials but not used in current clinical practice.”

Andrea Richardson, MD, of Brigham and Women’s Hospital, largely agreed with Dr. Silver on the need to identify molecular classifications of triple-negative breast cancer. She said that with BRAC1 gene expression as a clue, subsets of triple-negative breast cancer tumors might be revealed. Dr. Richardson also said that abnormalities in the tumor protein 53 (p53) gene might constitute a clue. “There is heterogeneity within the triple-negative molecular subtype for a number of genes and features of triple-negative breast cancer tumors,” she said, indicating groups of epithelial gene clusters that seem to show a distinct set of features in triple-negative breast cancer.

Dr. Richardson said relying on gene expression that identifies the 3 subtypes of breast cancer constitutes one way to classify the disease, but other subtypes exist that may allow more specific tailoring of treatment. She noted that oncologists have yet to reach a consensus on the nature of these subtypes: “The clinical significance of various subtypes within triple-negative tumors is a hotly debated issue and under active investigation.”

The desire to develop more effective treatments specific to an individual patient’s disease is what drives the search for biological markers that will allow physicians to differentiate between subtypes of triple-negative breast cancers. Martine J. Piccart-Gebhart, MD, Jules Bordet Institute, suggested that until these identifiers are found, practicing oncologists must find new ways to work with existing cancer-fighting tools. “While there are clearly emerging molecular targets for the treatment of triple-negative breast cancer which deserve our enthusiasm,” said Dr. Piccart-Gebhart, “the reality of today’s clinical practice is we mostly rely on chemotherapy.”

Dr. Piccart-Gebhart said that in her practice, a treatment she calls “metronomic therapy” has proven effective in patients with ER-negative breast cancer. This treatment involves prolonged administration of relatively low doses of a selected chemotherapy agent at close intervals rather than a large initial dose. She mentioned a small study on adjuvant chemotherapy in people with triplenegative breast cancer that used weekly doxorubicin, daily oral cyclophosphamide, and weekly paclitaxel (Taxol) plus carboplatin, but said that there was “no evidence to favor a particular chemotherapy at this time.”

All these oncology colleagues shared the view that if progress toward a treatment is to be made, researchers at various clinical trial sites need to be more forthcoming in offering their findings for comparison and contrast.

Hormones and insulin expression may guide future breast cancer treatments

Researchers have solidly established that the hormone estrogen contributes to cancer growth. Therapies like tamoxifen (Novaldex) block receptors of estrogen in ER-positive women and therefore inhibit the body’s ability to use the hormone. Tamoxifen is undergoing increasing scrutiny to determine whether it might also inhibit tumor angiogenesis (new blood vessel formation) by blocking the vascular endothelial growth factor (VEGF) receptor pathway.

Maura Dickler, MD, of Memorial Sloan-Kettering Cancer Center said that although therapies such as tamoxifen have proven effective in blocking VEGF in the clinical setting, particularly as a first-line treatment for ER-positive women, “recurrence remains a problem, as eventually the body becomes resistant to endocrine therapy.” Does this mean that angiogenesis plays a role in endocrine resistance? Some researchers say yes. One study that included 96 women found that those who were ERpositive and had high VEGF levels also had the lowest chance for recovery. Pilot studies in the very early stages indicate that anti-VEGF drugs may delay or prevent the onset of endocrine resistance in women with certain types of breast cancers.

A small phase II study is underway that combines bevacizumab (Avastin), a VEGF inhibitor, with letrozole (Femara), an aromatase inhibitor (AI). Whereas tamoxifen blocks a tumor’s ability to use estrogen, AIs reduce the amount of estrogen throughout the body. After 17 months of treatment, a clinically significant number of patients had PFS. “This was interesting,” Dr. Dickler said, “because many of the women had already been on AIs.” She concluded that VEGF mediates estrogen-induced angiogenesis and that an increase in VEGF encourages angiogenesis, contributing to endocrine-therapy resistance. Similar phase II and phase III trials are underway, as well.

In addition to studying VEGF inhibitors, oncologists are trying to determine whether inhibiting insulin-like growth factor receptors (IGF1R) can also combat tumor growth. According to Lyndsay Harris, MD, Yale School of Medicine, IGF1R is a “good target because it is ubiquitously expressed in all cancers, even if the signaling is not active.” Dr. Harris explained that IGF1R is present in all breast cancer cells, to some degree. “There’s no such thing as an IGF1R-negative breast cancer,” she said, “so it’s not a matter of whether [IGF1R] is present, but a matter of whether it is active and where it sits on the cell surface.”

Clinical trials are looking at drugs that target IGF1R in combination with trastuzumab. Early results indicate that inhibiting IGF1R raises the rate of apoptosis from 10% to 20% in trastuzumab- resistant tumors. Approximately 25 drug compounds that target IGF1R receptors are in development and currently under evaluation as potential cancer treatments, either in doublet or triplet therapies.

Can preliminary response guide the choice and course of sustainable treatment and predict long-term survival?

The ability to identify the status of a tumor as ER-, PR-, or HER2-positive has dramatically changed the way in which clinicians choose an initial treatment for their patients with breast cancer. Even if a tumor is found to be positive for one of these 3 receptors, this is not predictive of whether a patient will respond to a particular regimen. It is important that oncologists follow other clinical findings vigilantly when considering whether a treatment is working effectively, ideally in the neoadjuvant setting.

“Partial clinical response and clinical response are powerful early surrogates of long-term survival, but there is no baseline measure to accurately define response,” said Lajos Pusztai, MD, DPhil, of M. D. Anderson Cancer Center. “There’s just no such thing.”

According to Dr. Pusztai, a patient’s initial response to 2 cycles of chemotherapy, combined with knowledge of her hormone-receptor status, can help the oncologist determine whether the best possible therapy has been selected for the patient and what the next step should be. Tumor size at diagnosis and following neoadjuvant therapy, the extent of lymph node involvement, and cancer burden all hint at the patient’s prognosis for long-term survival.

“Pathologic clinical response is a strong predictor of survival for an individual, but do not confuse this with a survival rate in a clinical trial treatment arm,” Dr. Pusztai said, adding that “it’s important to remember that residual invasive cancer burden is a powerful predictor of long-term prognosis in an individual, but not [in] a group.”

Gunter von Minckwitz, MD, University of Frankfurt, uses ‘early clinical assessment’ as his measuring stick until conclusive molecular markers are available to guide treatment choice. After administering 2 or 3 cycles of neoadjuvant chemotherapy, Dr. von Minckwitz says his clinic performs ultrasonography or a mammogram to see whether the tumor has shrunk more than 50% from when it was first detected. “Then,” he said, “we might switch chemotherapy if needed.”

New Ways, New Drugs, and New Targets On the Horizon in Breast Cancer

Goserelin: Increasing the Dose to Decrease Dosing Frequency

Quality-of-life for people with breast cancer can be affected in many ways. One way to enhance it is through making therapy more convenient. Researchers are increasingly trying to find other ways to deliver an efficacious dose of chemotherapy to patients while making their lives easier. For example, goserelin (Zoladex), a gonadotropin- releasing hormone used to block the production of estradiol, is often used with tamoxifen to treat premenopausal women with early estrogen receptor (ER)-positive breast cancer. Typically, a 3.6-mg dose of goserelin is implanted subcutaneously in the patient’s body once a month for as long as her doctor deems necessary.

Iwata and colleagues conducted a multicenter, openlabel trial of 170 Japanese women with breast cancer to determine whether administering goserelin as a 10.8- mg dose would require less frequent administration yet deliver the same levels of the drug each month. Preliminary findings suggest that it did, but data on disease-free survival are not yet available.

Sorafenib (Nexavar) combined with anastozole may offset aromatase inhibitor (AI) resistance. Sorafenib, an angiogenesis/tyrosine kinase inhibitor that stops cells from dividing, is used to treat inoperable kidney and liver cancers. The drug is now under consideration as a possible enhancement to anastrozole (an AI) in patients with ER—positive and progesterone receptor (PR)–positive metastatic breast cancer (MBC). Subramaniam and colleagues hope that the combination will offset AI resistance, which is common in patients with MBC. According to preliminary results from this still-accruing clinical trial, adding sorafenib to anastrozole is thought to restore the patient’s sensitivity to AIs by creating an alternate pathway of delivery to tumor cells. In total, 27 patients have been enrolled in the study. Of these, 5 achieved a stable disease state for more than 6 months, 2 had partial response greater than 6 months, 10 had disease progression; others were not responseevaluable. Researchers believe the findings from this small study offer strong evidence that adding sorafenib to anastrozole in patients with ER/PR-positive and AI-resistant MBC is beneficial.

Nab-paclitaxel (Abraxane) may offer substantial advantages in breast cancer treatment. The need to find alternative ways to deliver anticancer agents to tumor cells—either to replace exhausted pathways or to help patients resistant after long-term use of a particular chemotherapy agent&mdash;has led breast cancer researchers to look at cutting-edge technologies. Nab-paclitaxel is a product of this search. Paclitaxel (Taxol) must be dissolved in a castor oil solution before administration and requires ~3-hour intravenous administration. Nab-paclitaxel, however, binds paclitaxel to the protein albumin, eliminating the castor oil step and bypassing a long list of potential complications associated with its intravenous administration. Patients enrolled in a phase III study of nab-paclitaxel also demonstrated nearly double the overall response rate and had significantly longer time to tumor progression compared with patients receiving traditional paclitaxel.

Results from a smaller ongoing study of nabpaclitaxel and bevacizumab (Avastin) plus gemcitabine (Gemzar) in patients with previously untreated HER2-negative MBC is currently underway. Gluck and associates have enrolled 22 patients in their study so far; 64% are ER—positive and 36% are PR–positive. Preliminary results show that 75% of patients have demonstrated partial response to the combination therapy. Investigators say findings indicate that, in the future, this triplet regimen may become an important first-line option for patients with MBC.

Updates on New Uses for Established Drugs and New Therapies on the Horizon

Capecitabine: New Combinations, New Ways of Administration

Breast cancer patients who develop metastatic disease likely have already undergone chemotherapy with agents such as anthracyclines or taxanes. After a period, patients may develop resistance to these and other drugs or perhaps they did not respond to them in the first place. Controlling metastatic breast cancer (MBC) in these patients presents a particular challenge for oncologists. At this point, the antimetabolite capecitabine (Xeloda) is often used in an attempt to prolong the lives of people with MBC. Researchers continue to explore additional uses for capecitabine in breast cancer treatment, however, such as combining it with new chemotherapeutic agents or using it in novel ways.

Ixabepilone (Ixempra) is a promising treatment for MBC patients who have stopped responding to treatment or are resistant to other therapies. Approved by the FDA late last year, it is the first epothilone—a bacteria-derived substance that disrupts cell division&mdash;approved to treat locally advanced breast cancer and MBC.

Two randomized phase III trials involving patients with MBC evaluated whether combination therapy with ixabepilone plus capecitabine was more effective than capecitabine alone. Hortobagyi et al enrolled patients resistant to anthracyclines (eg, daunorubicin, doxorubicin, and epirubicin), and the other study included patients who had been pretreated for MBC extensively, primarily with taxanes. According to investigators, adding ixabepilone to a regimen of capecitabine improved PFS, although the change in overall survival in both arms was slight.

In addition to chemotherapy’s adverse effects, keeping appointments for intravenous administration adds another burden that detracts from patients’ quality-of-life. A third capecitabine-related study examined the bioequivalence between different delivery schedules for the drug. Levy et al enrolled ~40 patients and allocated them evenly to 2 groups. One group was given the standard schedule for capecitabine treatment: 1250 mg/m2 twice a day for 14 consecutive days every 3 weeks. The other group received 1000 mg/m2 of capecitabine, twice a day, 5 days per week. After 3 cycles, the regimens for the 2 groups were switched, and all patients received 6 cycles in total. The study concluded that both schedules were safe, efficacious, and bioequivalent in the patients. This finding offers the potential to improve patients’ quality-of-life by freeing them from a grueling chemotherapy schedule.

Docetaxel: New Drug Combinations Show Promise in Early and Metastatic Breast Cancers

The mitotic inhibitor docetaxel (Taxotere) is traditionally used as adjuvant therapy in treating certain types of breast and other cancers, and new indications are always being sought out. Researchers recently studied whether docetaxel, alone or in combination with other therapies, would be effective in treating patients with early stage or metastatic breast cancers.

One phase II study involved patients whose tumors had been detected early and were removed, whose cancer had not spread to the axillary nodes, and who had not undergone adjuvant chemotherapy or radiation. Garcia Bueno and colleagues sought to discover the efficacy of a regimen often used in patients whose cancer has already spread to the axillary lymph nodes: docetaxel followed by doxorubicin plus cyclophosphamide. Of the 58 patients in the trial, 2 experienced disease progression within a median follow-up of just over 1 year. In total, 20% of patients suffered neutropenia after doxorubicin and cyclophosphamide were added to the regimen. Researchers concluded that, overall, the regimen was “feasible and well-tolerated as an adjuvant therapy for early stage breast cancer without axillary involvement.”

Key findings from the 2008 ASCO Breast Cancer Conference focus 
on the latest multidisciplinary research as well as in-depth
discussions on how and when to translate new findings into patient care. Highlighted presentations address the need for greater selectivity in choosing a therapy regimen for a specific patient with breast cancer. In particular, what efforts are underway to develop targeted treatments for triple-negative breast tumors?




Diane West

Articles

Politics & Policy: March 2007

The Rapid Reporter: June 2007

News Reports: June 2007

Pfizer's Innovative Oncology Division Is Right on Target

Beyond Genetics: Emerging Breakthroughs in the Breast Cancer Battle

Beyond Genetics: Emerging Breakthroughs in Breast Cancer Battle

Metastatic Breast Cancer Worldwide: Different Languages, Different Views, Different Goals