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Chemotalk Newsletter

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Let's get it on ...

The following is from CURE, my favorite publication relating to cancer treatment:

EARLY ACCESS TO NOVEL DRUG FOR HODGKIN'S LYMPHOMA PATIENTS IS IN THE WORKS*

By Elizabeth Whittington

    When we hear promising results of a new treatment, especially one that provides a new therapy option to patients who otherwise don't have any, we want to share that news with our readers. However, we do know that for a majority of patients, that news can't come soon enough. While the data may be promising, often patients are only able to get access to an investigational drug through a clinical trial, which may be limited to a single cancer center on the other side of the country. And it may be years until that agent is available to them as an approved drug.

    But for HODGKIN'S LYMPHOMA patients who have relapsed after an autologous stem cell transplant, there is hopeful news that brentuximab (SGN-35), a novel agent targets the CD30 antigen on the surface of Hodgkin's lymphoma cells, could be available via an early access program early next year.

    Seattle Genetics, the manufacturer of the drug, announced the program, which coincided with a press conference releasing results of a phase 2 trial with brentuximab. Although a date hasn't been given for the program's launch, CEO of Seattle Genetics Clay Seigall projected it could be early next year. This is in addition to Seattle Genetics submitting the drug to the FDA for approval in the next few months--not only for Hodgkin's lymphoma patients after TRANSPLANT failure, but also for RELAPSED/REFRACORY ANAPLASTIC LARGE CELL LYMPHOMA, a rare but aggressive type of non-Hodgkin's lymphoma.

    Dr. Robert Chen, at City of Hope in California, will be presenting his study results tomorrow at a session during the annual meeting of the American Society of Hematology. Some of the study results were presented at today's ASH press conference, including data showing 34 percent of patients had a complete remission with the drug. And after one year, the median duration of remission has not yet been reached--meaning that after one year, more than half of patients in complete remission have yet to relapse. Tumor shrinkage occurred in 94 percent of patients, with the response lasting a median of 29 weeks. More data will be available after tomorrow morning's formal presentation.

Brentuximab is administered as a 30-minute infusion and is not combined with other treatments, which limits its toxicity. However, about half of the patients in the trial developed peripheral neuropathy, which results in a stinging pain or numbness in the hands or feet. In most patients, the side effect went away once the drug was continued or treatment completed. Other common side effects included fatigue, nausea, upper respiratory tract infection and diarrhea. * It seems to be a matter of choice, whether to use "Hodgkin" or Hodgkin's", when referring to that particular course of lymphoma.  I've changed CURE'S choice, because it appears that "Hodgkin's" appears to be used more often. Sorry, CURE...But hey, they didn't review my book, so I have nothing to lose.)                        

* * *

WOMEN WITH MULTIPLE SCLEROSIS MORE LIKELY TO HAVE GENE MUTATION

    New research may help explain why MULTIPLE SCLEROSIS rates have risen sharply in the U.S. and some other countries among women, while rates appear stable in men.  The study could also broaden understanding of how environmental influences alter genes to cause a wide range of diseases.

    The causes of multiple sclerosis (MS) are not well understood, but experts have long suspected that environmental factors trigger the disease in people who are genetically susceptible.  In the newly published study, researchers found that women with MS were more likely than men with MS to have a specific genetic mutation that has been linked to the disease.

    Women were also more likely to pass the mutation to their daughters than their sons and more likely to share the MS-susceptibility gene with more distant female family members.

Gender Influences MS Gene

    If genes alone were involved, mothers would pass the MS-related gene to their sons as often as their daughters, says researcher George C. Ebers, MD, of the University of Oxford, in the U.K.  Ebers' research suggests that the ability of environmental factors to alter gene expression -- a relatively new field of genetic study known as epigenetics -- plays a key role in multiple sclerosis and that this role is gender-specific.

    The theory is that environmental influences such as diet, smoking, stress, and even exposure to sunlight can change gene expression and this altered gene expression is passed on for a generation or two.

    "The idea that the environment would change genes was once thought to be ridiculous," Ebers says. "Now it is looking like this is a much bigger influence on disease than we ever imagined."

    The study by Ebers and colleagues included 1,055 families with more than one person with MS. Close to 7,100 genes were tested, including around 2,100 from patients with the disease.  The researchers were looking for MS-specific alterations in the major histocompatibility complex (MHC) gene region.  They found that women with MS were 1.4 times more likely than men with the disease to carry the gene variant linked to disease risk.  A total of 919 women and 302 men had the variant in the MHC region, compared to 626 women and 280 men who did not have it.

    The study was published in Neurology.Genetic Alterations

    Epigenetics is not evolution. Genetic alterations linked to environmental assaults can be passed down for a generation or two, but DNA usually rights itself over time, Ebers says.  "This may explain why we hardly ever see MS in families over more than three generations," he says.

    Earlier studies by Ebers and colleagues suggest that vitamin D deficiency may be the environmental stressor that triggers the MS-linked gene alterations.  Rates of the disease are highest among people living farthest from the equator, and there is widespread speculation that lack of vitamin D due to low sun exposure may explain this.

    Other than Ebers' research team, Orhun Kantarci, MD, of the Mayo Clinic in Rochester, Minn., is one of the few researches studying epigenetics as it relates to multiple sclerosis.  Kantarci calls the new research a potentially important piece of the puzzle to explain the gender difference in MS, but he adds that the research must be replicated.

    "This study provides more questions than answers, but it is very interesting," he says. "We are learning that inheritance isn't as simple as [Gregor] Mendel described."

* * *

    How doctors choose to treat their BREAST CANCER patients -- and whether those treatment choices follow established recommendations -- may play a larger role in whether a cancer returns than experts have believed.  In a new analysis looking at 994 women with ductal carcinoma in situ, the most common type of noninvasive breast cancer, researchers found treatment variations from surgeon to surgeon are significant, and may account for up to 30% of recurrences.

    "Treatment variation is a troubling but well-known phenomenon in health care," said study author Andrew W. Dick, a researcher at RAND Corp. in Pittsburgh. The report is published in the Journal of the National Cancer Institute.  "The reason it is surprising in this case is that the variation is quite large, and related to factors that are very important in health outcomes," Dick said.

    Those factors include having "negative margins" -- meaning that cancer cells are more than 2 millimeters away from the removed tissue's edge -- and getting radiation therapy after breast-conserving surgery.

    The variation by surgeon in treatments accounted for 15% to 35% of cancer occurring in the opposite breast in the next five years and 13% to 30% of recurrences over 10 years, the investigators found.

    The study is well done, said Beth Virnig, a professor of health policy and management at the University of Minnesota School of Public Health and co-director of the Cancer Outcomes and Survivorship Program at the university's Masonic Cancer Center.  "They basically said, after taking into account all this stuff that matters -- how big the tumor is, its grade and which treatment -- it turns out a third of how the patient does is due to their physician," she said.  While Virnig is not surprised at the variations in treatments, the amount of variation surprised her.

    The findings are complex, she said, and so many factors determine outcome that there is no simple way to guarantee a woman has the best possible doctor and treatment.  One solution, said Virnig, is to develop a kind of scoring system for breast cancer surgeons. But she acknowledges that this may not be feasible.

    Meanwhile, she suggested that women can boost the odds of getting optimal treatment by asking their surgeon how many procedures the doctor does -- with more being better, though she can't provide a "good enough" number. "Many studies, but not all, show teaching institutions are better" when it comes to breast cancer treatments, she said.

    If a scoring system were developed, said Dick, "I would like the system to evolve in such a way that the consumer doesn't have to be the fully informed expert."  Meanwhile, he said, women facing breast cancer should get their doctors' views on radiation therapy after breast-conserving surgery and the importance of negative margins -- both of which are associated with a lower risk of recurrence.

* * *

SMOKING MAY INTERFERE WITH RHEUMATOID ARTHRITIS TREATMENT

    People with early RHEUMAROID ARTHRITIS (RA) who smoke are less likely to respond to treatment with two of the most commonly used medications -- an older disease modifying anti rheumatic drug called methotrexate and biologic drugs known as TNF blockers, according to a new study in Arthritis & Rheumatism.

    RA is an autoimmune disease that occurs when the body's immune system misfires against its own joints and tissues, resulting in inflammation, swelling, pain, and ultimately the loss of mobility. Treating RA early with disease-modifying anti rheumatic medications is considered the best way to stop this progressive disease in its tracks.

    "Our findings indicate that cigarette smokers have a diminished chance of responding well to the currently first- and second-line agents of choice in early RA treatment today," conclude researchers who were led by Saedis Saevarsdottir, MD, PhD, a rheumatologist at the Karolinska University Hospital in Stockholm, Sweden.

    Exactly how smoking affects response to RA treatment is not fully understood, but one theory suggests smokers may metabolize some RA medications differently than nonsmokers, which could compromise its effectiveness.

    Of 1,430 people with early RA who were part of a Swedish registry, 873 started therapy with methotrexate and 535 started taking anti-TNF drugs within about three years of their RA diagnosis.  If they smoked (27% of them were current smokers), participants were less likely to show a good response to treatment with methotrexate or anti-TNF drugs at three months, six months, one year, and five years out when compared with their counterparts who never smoked.

Past Smokers

    Those study participants who had smoked in the past did not experience a muted response to treatment when compared to those individuals who never smoked, the study showed.

    Treatment response was based on guidelines put out by the European League against Rheumatism (EULAR), the European equivalent of the American College of Rheumatology, and based on the number and degree of painful joints and other measures of disease activity.

    It is still too early to tell whether quitting smoking will improve response to therapy, but it seems plausible based on the fact that past smokers responded as well to therapy as never smokers, the researchers write.  "The findings provide a strong impetus for clinicians to include measures against smoking as a fundamental part of their therapeutic armamentarium in RA care," the researchers write.

    Exactly how smoking affects treatment response is not fully understood, he says. "Likely, it causes chronic inflammation which exacerbates the underlying problem in RA and limits response to therapy. Patients who smoke should definitely stop, but it may be particularly difficult given the stress of a chronic disease as well as potential effects of nicotine on pain perception."

More Reasons to Quit Smoking

    Previous research has shown that smoking can raise the risk for developing RA, says Theodore Fields, MD, clinical director of the Early Arthritis Initiative at the Hospital for Special Surgery in New York City. "If you are at risk for RA, such as having RA in your family, don't smoke because it does seem to be associated with onset and some data also suggest that it worsens RA that is already there."

    "This new study suggests that if you are a smoker, you are less likely to respond well to the most commonly used drugs. So the message is, if you are at risk of RA, don't smoke -- and if you already have RA, stop smoking," he says. "We can't say that stopping short-term will make you respond better, but the data is suggestive. The fact that people who were still smoking did worse suggests that it's a good idea to stop."

    "This is a very interesting study that provides further information on the impact of smoking on RA," says David Pisetsky, MD, chief of rheumatology at Duke University Medical Center in Durham, N.C.  This new information may help people with RA quit smoking, he says. "Smoking is bad for your lungs and for your heart, but you are less likely to respond to RA treatment, and that may be one more stimuli for a patient to stop."                                * * *

From The New York Times:

CANCER CAN DEVELOP IN CATASTROPHIC BURST

By Nicholas Wade

    New rapid methods of decoding DNA have brought to light a catastrophe that can strike human cells: a whole chromosome may suddenly shatter into pieces.

    If the cell survives this disaster, something worse may ensue: the cell becomes cancerous.

    The finding marks a striking exception to the current theory of how CANCER develops.  Cells are thought to become cancerous over many years as they collect, one by one, the mutations required to override the many genetic restraints on a cell's growth.  It now seems that a cell can gain all or most of these cancerous mutations in a single event.

    The discovery is reported in the publication Cell by a team led by Peter J. Campbell of the Sanger institute near Cambridge, England.

    The institute is part of a consortium with the National Institutes of Health in the United States to study the genomes of different types of cancer cells, a task now brought within reach because of fast and cheap methods for decoding DNA.  The hope is to identify the causative mutations that drive each type of cancer.

    As part of this project Dr. Campbell, a hematologist, was scanning the genome of 10 patients with a certain kind of leukemia.  Cancer cells lose control of their chromosomes, and their genomes are often a chaotic hodgepodge in which the chromosomes are rearranged, with some segments duplicated and others lost.  In one of his patients, Dr. Campbell noticed an unusual feature: almost all of the damage was confined to a single chromosome.

    By reconstructing the exact pattern of chromosomal rearrangements, he and colleagues found it could not be explained by the standard process in which one mutation is acquired after another in a protracted series. Rather, the chromosome must have shattered into pieces in a single event; the cell then knitted them together as best it could, but in the wrong order.

    Usually a cell that suffers this much damage will destroy itself, either immediately or after it has tried unsuccessfully to repair its chromosomes. But in certain cases, the self-destruct mechanism evidently fails, leaving a cell like Frankenstein's monster, with badly patched-up chromosomes but a survival advantage that leads to unrestrained growth.

    Dr. Campbell's group reports that about 2% to 3% of all cancers, and 25% of bone cancers, originate in this kind of chromosome-shattering crisis.

    "It's very hard to explain why the damage is so catastrophic but so localized," Dr. Campbell said, referring to the fact that almost all the damage occurs in a single chromosome or chromosome region.  His best guess is that the damage is caused by a pulse of radiation.

    Bone cancer is sometimes treated with radioactive isotopes that home in on the bone, which might explain why so many cases of bone cancer arise this way.

    But Matthew Meyerson and David Pellman, two cancer biologists at the Harvard Medical School, say in a commentary that the chromosomes could shatter accidentally when they condense, a process that happens before the cell divides.  Whatever the cause of the shattering, the find "reveals a new way that cancer genomes can evolve," they write.

    The discovery has no immediate implications for therapy  But it could explain why a few cancers, contrary to the usual rule, appear very suddenly. "There are clearly examples where someone has had a normal mammogram, then presents shortly after with an aggressive tumor," Dr. Campbell said.

* * *

An interesting animal story that may have future human consequence:

CANINE TUMOR FUELS UP BY STEALING PARTS FROM HOST, REPORT SAYS

By Carl Zimmer

    When humans domesticated dogs at least 10,000 years ago, an apparent side effect was a bizarre new kind of parasite.  A canine CANCER gained the ability to spread from one dog to the next, creating new tumors along the way.

    Today, it thrives in dog populations around the world.  Scientists are now studying canine transmissible venereal tumors (or C.T.V.T.) to uncover the adaptations the disease uses to thrive in its peculiar way.  In the current issue of Science, British scientists report that it upgrades its energy supply by stealing new parts from its canine hosts.

    The Russian scientist M. A. Novinsky first discovered C.T.V.T. In 1876. He found that when he transplanted the tumors from one dog to another, they could take hold and grow.  But the idea that cancer cells could travel from one host to another was too strange for many to accept.  Some scientists argued that some kind of virus caused C.T.V.T., much like human papillomavirus causes cervical cancer.

    In recent years, scientists have begun to study the genes of C.T.V.T. Cells, and their results have confirmed that it is indeed an infectious cancer.  In the last decade, two teams of scientists -- one based at Imperial College London and another at University College London -- independently gathered samples of C.T.V.T. from dogs around the world.  They sequenced snippets of their DNA and discovered the tumors were closely related to tumors in other dogs, not to the healthy cells in the host dogs.

    After they analyzed the mutations in different cells, both teams concluded that the tumors descended from an ancestral cancer that existed within the past few centuries.  But the Imperial College team also looked further back, to when a healthy cell first turned cancerous.  They estimated the transition happened several thousand years ago -- perhaps coinciding with the domestication of dogs.

    "It's an asexual, single-celled mammal, in a sense," said Austin Burt, a member of the Imperial College team.  "We talk about calling it Canis cancer."

    Scientists have discovered only one other case of infectious cancer Tasmanian devils can become infected by facial tumor hen they bite each other.  Researchers have proposed that the Tasmanian devils are vulnerable to the cancers because they have little genetic variability.  Tumors may be too similar to a devil's own cells to be rejected.

    When dogs first evolved from wolves, they had little genetic variation. "There weren't too many friendly wolves around," said Clare Rebbeck, a colleague of Dr. Burt's who has since moved to Cold Spring Harbor Laboratory in New York.  Dogs then exploded in numbers and diverged into many different breeds.  But C.T.V.T. today can infect them all.

    To get a more detailed look at the history of C.T.V.T., Dr. Rebbeck and her colleagues turned their attention to a second source of DNA in the tumors.  Every animal cell contains structures called mitochondria that produce the cell's fuel.  Mitochondria also contain a small amount of their on DNA.

    When the scientists compared pieces of DNA from the mitochondria, they were surprised to find that some samples were more closely related to genes from healthy dog cells than from other tumors.  In other words, the mitochondria in C.T.V.T. cells do not all descend from a common ancestor.

    Dr. Burt and hi colleagues propose that C.T.V.T. sometimes grab mitochondria from the dogs they infect.  They speculate that fresh nitochondria could come in handy, because their on mitochondria would acquire mutations, making them worse at generating fuel.  Cells that upgraded their mitochondria could grow faster.  "This paper is very interesting and exciting," said Elizabeth Murchison, a geneticist at the Wellcome Trust Sanger Institute in Britain.  Dr. Murchison is currently sequencing entire C.T.V.T. Genome and expects to finish the project later this year.

    "I'm curious to see the genome sequence," Dr. Burt said.  He expects many more adaptations will turn up.  "How many genes has it even able to get rid of?  Brain genes aren't needed anymore."

* * *

INFANT ORGAN DONORS COULD HELP MEET TRANSPLANT NEEDS: STUDY

    The organs of about 8% of infants who suffer cardiac death in newborn intensive care units (NICUs) would be eligible for donation and could help save the lives of other infants and young children, according to a new study.

    Children younger than 1 year old account for about 100 of the more than 200,000 people in the United States on an ORGAN TRANSPLANT waiting list. But currently, infants and young children who need an organ transplant can only receive an organ from an older child or part of an adult organ.

    In addition to the challenge of fitting a larger organ into an infant's body, demand for adult organs exceeds supply, noted Dr. Richard Parad, a neonatologist in the newborn medicine department at Brigham and Women's Hospital (BWH), and his colleagues at Children's Hospital Boston and Beth Israel Deaconess Medical Center.

    "A key motivation behind this study was our inability to act, under current guidelines, on the direct requests from parents faced with the loss of their newborn who turned to us wanting their child to be an organ donor," Parad said in a BWH news release.  These parents want some good to come from their tragic loss, he added.

    In this study, the researchers analyzed 192 deaths that occurred in the NICUs of three academic medical centers between 2005 and 2007. Eligibility for organ donation was based on criteria developed with transplantation surgeons and the New England Organ Bank.  Of the 192 infants who died, 14 livers, 18 kidneys and 10 hearts may have been eligible for donation, the researchers concluded.

    The researchers said their main objective was to provide data regarding the availability of infant donors. "Further investigation into this potential falls to those in the fields of transplant medicine and ethics. We feel we owe it to the families who request organ donation to be part of the conversation by investigating the size of the potential donor population," said study co-author Dr. Anne Hansen, of Children's Hospital Boston.

* * *

Another rare piece about transplants, from The New York Times:

AS U.S. PATIENTS AWAIT ORGAN TRANSPLANTS POTENTIAL DONORS STRUGGLE FOR VISAS

    The clock is ticking for D. Gabriel Danovitch's patient.  Dr. Danovitch, a TRANSPLANT surgeon at the David Geffen School of Medicine at the University of California, Los Angeles is treating an immigrant from Mexico in his 40s whose kidneys have failed.  The patient is a good candidate for a transplant and has a donor his brother.

    But there is a big problem: His brother is a Mexican citizen whose application for a visa to come to the United States was not granted.

    Physicians who perform transplants say patients ho need organ donations from a family member or other close match outside the United States face hurdles that are often hard to surmount.  Difficulties in obtaining visas leave many potential donors frustrated and force their sick relatives in the United States to ait months or even years on a list for organs like a liver or kidney.

   In other cases, poor families cannot afford to pay for the donors to travel to the United States and undergo organ-removal operations that can require hospital stays of up to three weeks.  In some states, Medicaid does not cover any of the donor's expenses, and private insurance policies vary greatly in how much they will cover.

    Getting organ donations is always difficult but medical authorities say the problems have gotten worse for immigrants with the tightening of visa policies after the terrorist attacks in 2001.  And with the slowdown in the economy, some states have been cutting back financial aid to transplant patients and donors.

    "If there is someone living and willing and compatible, it's concerning that, because of so much protection, they end up not being able to help a desperate person in need," said Bryan Stewart, a spokesman for One Legacy, a non-profit organization that deals with organ and tissue donations in the seven-country greater Los Angeles area.

    Dr. Giselle Guerra, medical director of the Living Kidney Donnor Program at the University of Miami Miller School of Medicine, has similar concerns. "I wish I could get rid of all the bureaucratic red tape, and it would be nice for every donor to fit the criteria so we can stop adding to the waiting list" she said.

    More than 110,000 people were waiting, according to the United Network of Organ Sharing, a private nonprofit organization that manages the nation's organ transplant system under contract with the federal government.

    Over 60,000 of those on the list are black, Hispanic, Asian, American Indian Pacific Islander or describe themselves as multi-racial, according to the organ sharing network.  Of those, 6,229 are resident aliens in the United States, compared with close to 1,900 resident aliens in 2000. Undocumented immigrants are prohibited from the list.

    "When patients need a transplant most of the time, the first people they turn to is their families" said Dr. Juan Carlos Caicedo, a transplant surgeon and director of the Hispanic Transplant Program at Northwestern Memorial Hospital in Chicago.  "It becomes complicated when their families are not in the U.S. which in a lot of instances, that is the case."

    The State Department does not have a medical visa category, and people traveling to the United States have to qualify for the B-1/B-2 visa, more commonly known as the tourist visa.

    "Our embassies and consulates around the world do their best to assist visa applicants who are dealing with life or death situations in order to expedite their cases," stated a department official.  An individual applying for a visa for a medical reason can fill out a form requesting that the application be expedited.

    But some doctors say that they have contacted State Department officials on behalf of patients and even that has not sped up the process.  "When I call the consulates or embassies, they're not very cooperative", Dr. Guerra said.  "We try to be as concise as possible, but also explaining the urgency in the letters that we write, but it just continues to be a waiting game."

    Dr. Linda Chen, a transplant surgeon at the University of Miami Miller School of Medicine, said that for about the last five years, the State Department has required foreign donor candidates to get preliminary testing done in their hoe country.

    Blood-collection tubes are mailed to the candidates, and the filled tubes are mailed back for testing.  If the donor has the same blood type, there is a possibility that he or she could be a match with the patient, and the State Department will take that into consideration, Dr. Chen said.

    "But even with blood work." Dr. Chen said, "they don't give people visas sometimes."  Dr. Chen said she writes letters on a monthly basis.  But she cannot do that for patients whose donor relatives are in Cuba.  "Since the U.S. Does not have a relationship with Cuba, we cannot help them by writing a letter or sending tests over" Dr. Chen said.

    If patients cannot get the donor into the United States, their names go on the organ network's list to receive an organ from someone who has died. Waiting times for patients vary, and among the factors is a person's state of residence.  Patients in New York, for example, wait an average of seven to nine years, while people in Florida wait three to five years.

    The No. 1 transplanted organ is the kidney.  Hen one is needed but not readily available patients must go through dialysis.  Medicare spent $9.2 billion in 2009 on dialysis patients, according to an annual Medicare Payment Advisory Commission report due to Congress in March.  Martha Escamilla-Arias, a social worker at Northwestern Memorial Hospital said that in most cases dialysis cost the State of Illinois more than a kidney transplant in the long run.

    "In Illinois, to and a half years of dialysis pays for one kidney transplant" Ms. Escamilla-Arias said.  "Some people are in dialysis for five to seven years, and if things ere easier for foreign donors it would help."

    Jean Viera, 34, a Cuban immigrant on the organ network's list, has been going through dialysis for six years.  His left arm is disfigured with two purplish raised scars where he is connected to a dialysis machine.

    "I wish I did not have to go through this," Mr. Viera said.  "This is just not the best way to live."

* * *

More from The New York Times, a follow-up to last month's melanoma story:

DRUG TO FIGHT MELANOMA PROLONGED LIFE IN TRIAL

By Amy Harmon

    Advanced MELANOMA patients taking an experimental drug aimed at a particular mutation in their tumors lived longer than patients who did not receive the drug in a decisive clinical trial, said Roche, the drug's manufacturer.

    The results pave the way for Roche to seek approval to market the drug, which shrank tuors for an average of six months in earlier trials but had not yet been proven to prolong survival.  Developed by Plexxikon, a small biotechnology company in Berkeley, Calif., it is based on an understanding of cancer's most basic molecular workings that is seen as a potential key to providing more lasting treatments for melanoma and other cancers.

    "In the past, with chemotherapy, we were grasping at things," said Dr. Paul Chapman, an oncologist at Memorial Sloan-Kettering Cancer Center who led the trial.  "No we have a rational way of building on this.  For the first time, we can see the path forward."

    About half of the 68,000 Americans who develop melanoma every year have a mutation in the gene, called B-RAF, that goes awry, for reasons not well understood, signaling cells to grow uncontrollably.  The Roche drug works by blocking the malfunctioning protein the gene produces in cancer cells but leaving the functioning proteins in non cancerous cells alone.

    In the drug's earliest trial, nearly every patient whose tumor cells contained the B-RAF mutation responded to the drug.  That marked a radical difference from standard CHEMOTHERAPIES, whose reason for working in certain patients and not others is not well understood.

    It also led some oncologists to assail the ethics of the trial, because it requir3d some patients who might have been helped by the new drug to instead take a chemotherapy drug that was seen as essentially a placebo. Starting in January of 2010, 338 patients were assigned to the chemotherapy arm of the trial, while another 338 received the Roche drug.

    A series of articles in The New York Times last year described the early testing of the drug and the debate among oncologists over the design of the latest trial.

    To measure whether the drug prolonged lives, the company was to compare survival on both arms of the trial.  A Food and Drug Administration spokeswoman said that the agency asked the company to perform that analysis sooner than originally planned.  Patients on the chemotherapy arm of the trial will now be able to "cross over" and receive the drug.

    Melanoma the deadliest form of skin cancer has been essentially untreatable after it spreads with a median survival rate of eight months from the time of diagnosis.  Roche has not yet reported how much longer patients taking the drug live on average.

    The company has opened an "expanded access" program at three cancer centers to provide the drug for melanoma patients who are not enrolled on the trial.

    But even as patient advocates and oncologists elcomed the results of the Roche trial, they called for more expedient testing of drugs to combine with it.  Research into why patients ultimately relapse after responding to the drug is pointing to other drugs similarly tailored to particular mutations that could yield more durable benefits for patients.

    "Combining drugs is where the future of oncology treatment lies" said Timothy Turnham executive director of the Melanoma Research Foundation, a nonprofit advocacy group.  "We need companies to cooperate and make this happen now."

* * *

A story of particular interest to those of us with Stage 4 cancer:

A PINK-RIBBON RACE, YEARS LONG

By Roni Caryn Rabin

    By the time Suzanne Hebert realized that her doctor was wrong and that the hard lump in her breast wasn't a normal part of breast-feeding, the tumor was the size of a stopwatch and the CANCER had spread to her spine.

    Still, Dr. Hebert, an optometrist in South Windsor, Conn., went to her first support group meeting thinking that as bad as things were, at least breast cancer was not an obscure disease; she would not be alone.

    But the room was filled with women who had early localized cancers.  Some had completed CHEMOTHERAPY years ago; they were "survivors."  When one newcomer asked Dr. Hebert for her story, she couldn't bring herself to tell the truth.

    Although great strides have been made to the treatment of breast cancer, recent events, including Elizabeth Edwards' death last month and the government's decision to ban the drug Avastin as a treatment for metastatic breast cancer, have drawn attention to the limits of medical progress -- and to the nearly 40,000 patients who die of the disease each year.

    Of women who are given a diagnosis of breast cancer, only 4% TO 6% are at Stage 4 at the time of diagnosis, meaning the cancer has already metastasized, or spread, to distant sites in the body.  But about 25% of those with early-stage disease develop metastatic forms, with an estimated 40,000 new diagnoses each year, according to the American Cancer Society.

    At least 150,000 Americans are estimated to be living with metastatic breast cancer -- including Dr. Hebert, now 45, who got her diagnosis six years ago and no works with the nonprofit Metastatic Breast Cancer Network.

    Stage 4 breast cancer can be treated, but it is considered incurable.*  Depending on the type of tumor, patients may live for many years -- working, raising children, starting nonprofit foundations, doing yoga and even running half-marathons.

    But theirs are not pink-ribbon lives: They live from scan to scan, in three-month gulps, grappling with pain, fatigue, depression, crippling medical costs and debilitating side effects of treatment, hoping the current therapy will keep the disease at bay until the next breakthrough drug comes along, or at least until the family trip to Disney World.

    "This woman had just been diagnosed," Dr. Hebert said of her support-group encounter, "and I couldn't bring myself to tell her: 'I have it in my bones.  I have it in several parts of my body.  My treatment is never going to end.'

    "It as a horrible moment," she went on.  "I had nothing in common with them.  I was what scared them."

    While perceptions of the disease may have changed in recent years, the number of death it causes has remained fairly static, said Dr. Eric P. Winer, director of the breast oncology center at the Dana-Farber Cancer Center Institute in Boston.

    "All too often, when people think about breast cancer, they think about it as a problem, it's solved, and you lead a long and normal life; it's a blip on the curve," he said.  "While that's true for many people, each year approximately 40,000 people die of breast cancer -- and they all die of metastatic disease.  You can see why patients with metastatic disease may feel invisible within the advocacy community.:

    Many patients keep the spread of their disease private, and Mrs. Edwards's 2007 announcement that her cancer had become "incurable" was an inspiration to many -- it was also why her death was such a blow.

    "She put a face on the disease," Dr. Hebert said.  "I could explain my situation to people."

    "The day she stopped treatment was very emotional," she added, "because I've been telling people 'I'm like Elizabeth Edwards.'"

    Mrs. Edwards's husband, the former senator and presidential candidate John Edwards, referred to her illness as a "chronic" disease, implying that it was manageable.  In fact, however, the median life expectancy for patients with metastatic breast cancer is just 26 months, and fewer than 1 in 4 survive for more than five years.

    But because breast cancer is a complex illness that encompasses many subtypes, generalizations are tricky.  Ne drug treatments are keeping some patients alive for a decade or more, even after the disease has spread.

    And they can enjoy a higher quality of life than patients did in the past, because treatments are better focused and have fewer side effects.  The prognosis has especially improved for patients with certain aggressive cancers, like HER-2 positive, that were considered extremely difficult to treat until recently.

    "Over the past 20 years, we've had probably 15 new drugs approved by the F.D.A., and each of them adds an incremental amount to the length of life," said Dr. Gabriel N. Hortobagyi, director of the breast cancer research program at M.D. Anderson Center in Houston.

    The average patient may receive eight or 10 different treatment regimens in sequence, he said.

    "I would never tell a patient with a newly diagnosed metastasis that there is nothing I can do," he said, "because there are actually dozens of things I can do -- whether it is hormone therapy, whether it is Herceptin, whether it is irradiation therapy or single agent chemotherapy -- and there are many things we can do to control symptoms and prevent complications."

    But treatment at these advanced stages is an art as well as a science, involving "a certain amount of trial and error," said Dr. James L. Speyer, director of the Cancer Center at N.Y.U. Langone Medical Center.  "You try a treatment, based on your best knowledge about the patient and the features of the cancer, and if it's working, great -- you continue it unless the side effects are a problem," he said.  "And if it's not working, you stop and try again."

    Patricia McWaters, who lives in Missouri City, Tex., a suburb of Houston, had frequent mammograms but did not learn she had breast cancer until it appeared in her liver and spine in 2003.  Now 71, she has had nine treatments at M.D. Anderson, including combination chemotherapy, drugs that block estrog3en production, more chemotherapy followed by a chemo drug that comes in pills, and now a ne, more aggressive drug.  "Whenever anything quits woring and a spread is starting, then we change," she said.

    In some cases, metastatic breast cancer appears to go into long-term remission, but experts say that in most cases it will recur, eventually becoming resistant to all treatment.

    Since it is metastasis that ultimately kills, some advocates want more resources devoted to its study and treatment.  Even though many cancer drugs are initially tested on patients with advanced disease, Danny Welch, an expert on metastasis, says only a few hundred scientists in the world are trying to understand the process.

    "It's responsible for 90% of the morbidity and mortality, but gets less than 5% of the budget," said Dr. Welch, a senior scientist at the Comprehensive Cancer Center at the University of Alabama at Birmingham, who studies genes that suppress metastasis.  (Those genes are turned off when cancer is advanced.)  "Funding agencies as a rule want to say their research portfolio is successful -- they want a return on their investment very quickly."

    Patients with metastatic disease are frustrated because they are often barred from clinical trials if a certain number of chemotherapy regimens have failed to work for them.

    When they find a drug their tumor responds to, they can achieve a remarkable degree of stability.  Pat Strassner, 61, of Severna Park, Md., had breast cancer that spread to her lung and hip in 12007, but she has had success with a chemo pill called Xeloda for the past three years.  The drug has side effects, including drying out of the skin on her hands and feet so much that they crack and bleed, but Ms. Strassner is still able to enjoy running, and last month she completed a half-marathon with her husband in Charlotte, N.C.

    Other drugs are proving more problematic.  Last month the Food and Drug Administration announced that it was withdrawing approval for Avastin in metastatic breast cancer after four studies found that it did not prolong survival and led to life-threatening risks, including heart attack and heart failure.

    Christi Turnage, 48, of Madison, Miss., who has been using Avastin for two and a half years, said she was terrified about losing access to it.  "This drug is literally keeping alive," she said.

    This kind of uncertainty keeps many patients from throwing themselves wholeheartedly into the ethos of hope and empowerment that helps sustain many women with less aggressive forms of the disease.

    Dr. Hebert says that while the pink-ribbon campaign has raised awareness about breast cancer, it masks a relentless killer.

    "People like the pretty story with the happy ending," she said.  "We don't have the happy ending.

    "You always hear stories about women ho 'battled it' and 'how courageous' they were.  Cancer doesn't care if you're courageous.  It's an injustice to all of us ho have this.  There are women who are no less strong and no less determined to be here, and they'll be dead in two years."

*It's strange to have to say this yet again, but there is no cure for cancer.  I know a woman diagnosed "Stage Zero", whose cancer metastasized. The idea that some cancers can be cured can give a false sense of security to anyone who has received the message that they've been "cured", just as those who have been told that they can't be cured very often live in a state of fear.  It should also be remembered that not every Stage 4 diagnosis is breast cancer.  Metastatis in other cancers is just as deadly as breast cancer, and deserves far more of the share of research dollars than it receives.

    Finally, a reasonable assessment of Avastin and its application to breast cancer, calling into question the FDA's recent decision, and causing all of us diagnosed with advanced breast cancer if an option that could save our lives is being precipitously removed:

MORE EVIDENCE LINKS AVASTIN TO HEART FAILURE IN BREAST CANCER PATIENTS

    Just weeks after U.S. health officials moved to rescind approval of the drug Avastin to treat BREAST CANCER, a new study provides more evidence that the anti-cancer medication ups the odds of congestive heart failure in these patients.  The meta-analysis, published in the Journal of Clinical Oncology, included almost 4,000 patients and found a small but significant number developed heart failure.

    Last month, the U.S. Food and Drug Administration announced plans to revoke approval of bevacizumab (Avastin) for treating breast cancer, although not for other indications. The move was based on evidence that the drug doesn't prolong overall survival in breast cancer patients and poses a risk of serious side effects.

    "What we see with Avastin in terms of its cardiac toxicity, frankly, it's not that unusual in cancer chemotherapy," said Dr. William Abraham, a heart failure specialist and director of cardiovascular medicine at Ohio State University Medical Center in Columbus, who is familiar with the study. "It turns out that many of the systemic anti-cancer treatments have detrimental effects on the cardiovascular system."

    According to Abraham, Avastin actually was less likely to cause heart failure than some other widely used breast cancer drugs, in particular the class of chemotherapy agents known as anthracyclines. But the FDA's decision was based on the totality of evidence, he said, citing possible side effects such as perforations of the nose, stomach and intestine; high blood pressure; and heart failure.

    The damage caused by Avastin appears to be reversible after the drug is stopped. Damage from anthracyclines is not, according to the study, conducted by researchers at the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

    In this new review of studies, which included 3,784 patients, 1.6% of patients taking Avastin developed heart failure, which the authors characterized as "reasonably low."  Yet the relative risk compared to placebo was almost five times as high in Avastin patients. No differences emerged between high and low doses of the drug.  By contrast, some 25% to 30% of patients taking Avastin develop high blood pressure, 5% of them severe hypertension, Abraham said. And about 4% to 5% develop blood clots, he added.

    "From the heart failure standpoint, Avastin is certainly no worse and in many instances better than some other chemotherapy agents that are used to treat cancer in general or breast cancer in particular," Abraham said. "But if you look at totality of data, hypertension, severe hypertension and thromboembolic [blood-clotting] events, there seems to be overall increase in cardiac deaths in these patients. When you take all of that together, it really raises the red flag."

    The issue of harm vs. benefit weighs heavily on the minds of cancer experts, they added.  "When we have drugs that have small values, which is what Avastin is in the therapeutic setting, we really better be sure that these drugs are helping our patients and not doing some harm," said Dr. Jay Brooks, chairman of hematology/oncology with Ochsner Health System in Baton Rouge, La.  "Unfortunately, Avastin has proved to be not as good as we thought it would be," he added. "It was put on the market on accelerated approval and when we do things quickly sometimes, when there's a huge push to get it out to the public, sometimes it backfires."

    Avastin's approval for treating breast cancer in 2008 was based on one clinical trial in patients with metastatic HER2-negative breast cancer that found a benefit in terms of cancer recurrence -- but not overall survival -- and was contingent on further data to confirm the results. Follow-up studies failed to confirm a survival benefit, which led to the FDA's unusual move in December.

    Avastin, made by Genentech, is also approved to treat COLORECTAL CANCER, NON-SMALL-CELL LUNG CANCER, high-grade gliomas (BRAIN TUMORS) and KIDNEY CELL CANCER. The recent FDA action does not affect these uses.  The study authors suggested that breast cancer patients might be more susceptible to side effects from Avastin than some other cancer patients because of prior or simultaneous use of other cardiotoxic drugs.

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at jesmer_e@pacbell.net

Elaine Jesmer

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