A nonanthracycline-containing chemotherapy regimen combined with the targeted therapy trastuzumab (Herceptin) may be an option for some women with HER2-positive breast cancer, according to results from the Breast Cancer International Research Group 006 (BCIRG-006) trial. These results, the first from a large randomized breast cancer trial to test nonanthracycline chemotherapy with trastuzumab, were reported October 6 in the New England Journal of Medicine. Read more > >
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Chemotherapy Less Toxic to the Heart May Be Option for Some Women with HER2-Positive Breast Cancer
Although they are effective anticancer drugs, anthracycline-based chemotherapy regimens and the targeted drug trastuzumab can cause heart damage.
A nonanthracycline-containing chemotherapy regimen combined with the targeted therapytrastuzumab (Herceptin) may be an option for some women with HER2-positive breast cancer, according to results from the Breast Cancer International Research Group 006 (BCIRG-006) trial. These results, the first from a large randomized breast cancer trial to test nonanthracycline chemotherapy with trastuzumab, were reported October 6 in the New England Journal of Medicine.
Anthracyclines are effective anticancer drugs, but they can produce long-term side effects, including heart damage and second primary cancers. Because trastuzumab can also cause heart damage, combining the two drugs may further increase the risk to the heart.
The nonanthracycline regimen tested in BCIRG-006 was based on laboratory data that showed synergy between trastuzumab and docetaxel or platinum-based chemotherapy drugs. “It was also anticipated that [the regimen] might circumvent the cardiac toxicity seen with anthracycline-based regimens,” wrote the study authors, led by Dr. Dennis Slamon, director of Clinical/Translational Research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.
Researchers in 41 countries enrolled 3,222 women with HER2-positive breast cancer in the trial. Participants were randomly assigned to receive one of three chemotherapy regimens after surgery: doxorubicin (an anthracycline), cyclophosphamide, and docetaxel (AC-T); AC-T plus trastuzumab; or docetaxel and carboplatin plus trastuzumab (TCH). The trial was sponsored by Sanofi-Aventis, the maker of docetaxel, with additional support from Genentech, the maker of trastuzumab.
At a median follow-up of 5.4 years, women in both groups receiving trastuzumab had better 5-year disease-free survival rates (84 percent for AC-T plus trastuzumab and 81 percent for TCH) than women who received AC-T alone (75 percent). The differences for both trastuzumab-containing regimens were statistically significant. (The researchers defined disease-free survival as the length of time without a breast cancer recurrence, a second primary cancer, or death from any cause.)
Although no significant difference in the rate of disease-free or overall survival was seen between the two trastuzumab-containing regimens, the study was designed to test both trastuzumab-containing regimens against treatment without trastuzumab, not against each other.
Therefore, there is no definitive answer to whether one of the trastuzumab-containing regimens is better than the other, explained Dr. Sally Hunsberger, an investigator with the Biometric Research Branch in NCI’s Division of Cancer Treatment and Diagnosis (DCTD). Instead, the authors looked at the tradeoff between disease-free events and cardiac events by comparing the excess of breast cancer events to the excess of high-grade congestive heart failure events.
A total of 144 women receiving TCH had a distant recurrence of their cancer compared with 124 women receiving AC-T plus trastuzumab (a difference of 20 events). However, 21 women receiving AC-T plus trastuzumab had high-grade congestive heart failure compared with 4 women who received TCH (a difference of 17 events). In addition, 18.6 percent of women receiving AC-T plus trastuzumab had a nonsymptomatic loss of heart function compared with 9.4 percent of women who received TCH.
Patients who receive TCH probably have a few more cancer recurrences, “but is it worth the cardiac events to use an anthracycline?” asked Dr. Hunsberger. Individual women and their doctors will need to decide which treatment is more relevant to their circumstances, balancing the risk of late side effects with the risk of recurrence, she said. “If a woman has heart disease, then TCH is probably a valid regimen to use.”
Taken together, the data from this trial “do not clearly favor one regimen over the other,” wrote Dr. Daniel F. Hayes of the University of Michigan Comprehensive Cancer Center in an accompanying editorial. “These observations establish TCH as another (but not ‘the’) standard of care for adjuvant treatment of HER2-positive early-stage breast cancer,” he concluded.
“I agree that both trastuzumab-containing regimens could be considered ‘standard’,” said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in DCTD. “This study confirms again that trastuzumab-based therapy—whether combined with TC or AC-T as a chemotherapy backbone—has marked benefits in patients with tumors that overexpress HER2.”
It will be important, said Dr. Slamon, to keep following these and other women who have received the combination of an anthracycline and trastuzumab to better understand the long-term effects on the heart. “We don’t have long-term safety data on a lot of these studies, and that’s a real problem,” he explained.
The BCIRG-006 researchers plan to follow their participants for a median of 10 years to gather additional data on efficacy and safety.
“I think [this] changes practice,” said the trial’s principal investigator, Dr. Jeffrey Bradley of the Washington University School of Medicine, during a news briefing.
The trial, conducted by the NCI-sponsored Radiation Therapy Oncology Group, initially compared a radiation dose of 74 Gy to the standard 60 Gy dose in combination with standard chemotherapy with or without cetuximab (Erbitux). The investigators stopped enrollment in the high-dose radiation arms of the trial in June 2011, after the interim analysis revealed that, based on the number of deaths (90) at that point in the trial, there was no statistical chance that overall survival would be improved in patients treated with the 74 Gy radiation dose.
At the time of the interim analysis, 423 patients were enrolled in the study. There were more deaths related to treatment in the high-dose radiation therapy arms (7 versus 3), but that discrepancy did not account for the lower survival in that patient group, the analysis found.
This trial was the first in three decades to compare different radiation doses in patients with stage III NSCLC that had spread no further than to nearby lymph nodes, Dr. Bradley explained. The trial is continuing with two arms, comparing radiation therapy at 60 Gy and chemotherapy with or without cetuximab.
Although the 60 Gy dose has been considered a standard for patients with stage III lung cancer, Dr. Bradley said, several studies conducted at single institutions had suggested that survival could be improved without additional adverse side effects by using a higher radiation dose. Dr. Tim Williams, a former ASTRO president from Boca Raton Regional Hospital, said the higher dose has been the standard at his hospital for the past 5 years.
The findings, said Dr. Giuseppe Giaccone, chief of the Medical Oncology Branch in NCI's Center for Cancer Research, strongly suggest that high-dose radiation therapy should be abandoned in this patient population.
BRCA Gene Mutations May Influence Survival, Treatment Response in Ovarian Cancer
Women with ovarian cancer who have a mutated form of the BRCA2 gene may be more likely to respond to standard chemotherapy and have better overall and progression-free survival than women without the mutation, according to a new study published October 12 in JAMA. The findings also suggested that women with BRCA1 mutations had better overall and progression-free survival than women whose tumors lacked the mutations, but these latter findings were not statistically significant.
To conduct the observational study, Dr. Da Yang of the University of Texas M. D. Anderson Cancer Center and his colleagues analyzed genomic and clinical data from the tumors of 316 women with high-grade serous ovarian cancer. The data were made available in 2009 and 2010 from the NCI-supported The Cancer Genome Atlas (TCGA) program. Most of the women in the study (219) had nonmutated forms of the BRCA1 and BRCA2 genes. Only 27 women had BRCA2 mutations, and 35 had BRCA1 mutations.
Overall, 61 percent of women with BRCA2 mutations were alive after 5 years compared with 25 percent of women with non-mutated BRCA1 and BRCA2 genes and 44 percent of women with BRCA1 mutations. All of the women with BRCA2 mutations responded to chemotherapy, whereas 85 percent of women with wild-type BRCA genes and 80 percent of women with BRCA1-mutations responded.
“Our observations provide evidence that BRCA1 and BRCA2 mutations are differentially associated with patient survival compared with [non-mutated] BRCA and that this difference may be a result of distinct response to platinum-based treatment and different associations with genome instability,” the study authors wrote. Because of the relatively small size of the study, they acknowledged, more research is needed to validate the findings.
The study results provide “a major advance” in the understanding of how to test new treatments in women with ovarian cancer, wrote Drs. Victor Grann and Ramon Parsons of the Columbia University Medical Center in an accompanying editorial. They cited, for example, clinical trials that could test PARP inhibitors in women with ovarian cancer to test whether patients with BRCA1 or BRCA2 mutations respond differently.
A larger, NCI-led study presented earlier this year at the American Association for Cancer Research annual meeting had similar findings, including improved overall survival in women with ovarian cancer whose tumors had BRCA2 mutations.
Newer Cancer Drugs May Cause Thyroid to Function Abnormally
Over the last decade, many patients with cancer have benefited from the development of new targeted therapies and immunotherapies. But a common side effect of these agents may be unintended effects on the thyroid gland, according to a report published online today in the Journal of the National Cancer Institute.
Ole-Petter R. Hamnvik of Brigham and Women’s Hospital and his colleagues reviewed the scientific literature on thyroid dysfunction and newer anticancer therapies. They found that thyroid dysfunction occurred in an estimated 20 percent to 50 percent of patients who received the newer therapies, which include tyrosine kinase inhibitors and immunotherapies such as ipilimumab.
A common side effect of the newer cancer therapies is hypothyroidism, which causes symptoms such as fatigue and constipation. These conditions are common among cancer patients and may therefore be difficult to distinguish from symptoms caused by the underlying malignancy or by medications used for symptom control. Symptoms of thyroid dysfunction can also be confused with other treatment-related toxic effects, which may lead doctors to reduce treatment dosages or frequency.
Hamnvik and his colleagues recommended that doctors closely monitor patients receiving these treatments for signs of thyroid dysfunction. “This may allow early recognition and treatment of thyroid disease, allowing continued treatment of the underlying cancer, as well as improving the quality of life of the patient,” they wrote.
The report’s authors also recommended that doctors monitor thyroid function in all clinical trials involving new anticancer agents.
More research is needed to understand the mechanisms of the thyroid abnormalities associated with these treatments and to explore the many unanswered questions in the field, the authors added, noting that most of the published data are from small or preliminary studies.
“Treatment for thyroid diseases is safe and likely to enhance patient quality of life, as well as potentially allow effective treatments for the underlying cancer to continue,” the authors concluded.
Bacterium Linked to Colorectal Cancer in Two Independent Studies
Two independent research groups have identified a bacterium that is associated with colorectal cancer in the first studies to identify a potential link between this common cancer and an infectious agent. Further research is needed, however, to validate the findings and determine whether the bacterium plays a causative role in colorectal cancer, researchers from both groups stressed. The studies were published online October 18 in Genome Research.
The microbe Fusobacterium is not abundant in the human colon, which houses trillions of bacteria and thousands of microbial species. Nevertheless, Fusobacterium species have been associated with a number of conditions, including inflammatory bowel diseases, such as ulcerative colitis, an established risk factor for colorectal cancer.
The two research groups used similar approaches in their studies. A British Columbia Cancer Agency team, led by Dr. Robert Holt, initially identified an overabundance of Fusobacterium by analyzing 11 colorectal tumor samples and adjacent healthy colon tissue from the same patients using high-throughput RNA sequencing. A group from the Broad Institute at the Massachusetts Institute of Technology and Harvard University, led by Dr. Matthew Meyerson, used whole-genome sequencing to identify bacterial DNA in 9 paired cancerous and normal colon tissue samples.
Both groups used polymerase chain reaction (PCR) technology to validate the findings in a larger group of paired cancerous and normal colon tissue samples (88 and 95 samples, respectively).
Among the samples analyzed by Dr. Holt and his colleagues using PCR, “the mean overall abundance of Fusobacterium was found to be 415 times greater in the tumor samples…than in the matched normal samples,” they reported. Although Dr. Meyerson’s group had similar findings, “only a subset of the cancers showed dramatic enrichment of Fusobacterium species,” they noted.
Dr. Meyerson and his colleagues also found Fusobacterium in 2 out of 11 samples of colorectal cancer metastases.
“The presence of this bacterium may simply represent an opportunistic infection at an immunocompromised site, but the possibility of a role in tumor etiology, perhaps through pro-inflammatory mechanisms, deserves further scrutiny,” Dr. Holt and his colleagues wrote.
The bacterial composition of the tumors analyzed and their matched control tissue were more similar to each other than the bacterial composition of tumor samples from different patients, noted Phil Daschner of NCI’s Division of Cancer Biology. This suggests that “a patient’s gastrointestinal ecosystem—including the individual’s genetics, other bacteria, and cellular- and dietary-derived components and metabolites—is more important in shaping the microbial communities in the tumor than the tumor's microenvironment,” he continued.
The findings also suggest the possibility that prevention, diagnosis, and treatment strategies could be formulated based on the colon’s bacterial makeup, Daschner noted.
Vitamin E Supplements Tied to Increased Risk of Prostate Cancer
A new study shows vitamin E supplements are associated with a higher risk of prostate cancer.
Men in a large prostate cancer prevention trial who took vitamin E supplements had a higher risk of developing the disease than men who took a placebo, according to extended follow-up of trial participants. Dr. Eric Klein of the Cleveland Clinic and his colleagues reported the finding October 12 in JAMA.
At the time, participants were told to stop taking the supplements, and researchers continued to follow the men. The interim analysis also suggested that vitamin E might be associated with an increased risk of prostate cancer, though the result was not statistically significant at the time.
But with additional follow-up, the researchers detected a 17 percent increased risk of prostate cancer among men who took 400 international units of vitamin E per day (IU/d) compared with men who took a placebo, a difference that was statistically significant.
The Evidence on Vitamin E
In reporting their results, the researchers noted that, by and large, vitamin E has failed to show a benefit for preventing a number of diseases. “The totality of the evidence shows that vitamin E does not prevent other diseases, and we now have evidence that it may increase the risk of prostate cancer,” said Dr. Klein.
Consumers need to be skeptical of health claims for over-the-counter products when strong evidence of a benefit demonstrated by clinical trials is lacking, the study authors stressed.
“Studies like SELECT make us take a step back and realize that any pharmaceutical agent we give has the potential for benefit and, as remote as it may be, also the potential for harm,” said co-author Dr. J. Michael Gaziano of Brigham and Women’s Hospital.
The totality of the evidence shows that vitamin E does not prevent other diseases, and we now have evidence that it may increase the risk of prostate cancer.
—Dr. Eric Klein
“That’s why we engage in these large-scale randomized studies, especially for agents that are in widespread use,” he added.
More than half of all men over age 60 in the United States are taking supplements containing vitamin E, and 23 percent are taking the dose used in SELECT, the study authors noted. Therefore, the finding of an increased risk of prostate cancer has “substantial implications.”
The increased risk of prostate cancer emerged only after the men had stopped taking the supplements. “These agents seem to have longer-lasting effects,” said Dr. Klein, noting that researchers who design clinical trials need to consider this possibility.
“This study is yet another cautionary tale about the potential risks of high-dose nutritional supplements,” said Dr. JoAnn Manson of Harvard Medical School, who was not involved in the research. “We’ve seen this before, and it shows why it is so important to have these randomized trials.”
In the early 1980s, she noted, beta-carotene was widely regarded as “a magic bullet for good health” until clinical trials showed that it was harmful to those at elevated risk for lung cancer, particularly smokers.
Another large randomized trial, the Physicians Health Study II, linked vitamin E to an increased risk of bleeding-related strokes.
Although deficiencies in certain nutrients can cause health problems, high doses of supplements may have health risks that outweigh the benefits, noted Dr. Manson, who is leading a large randomized trial of vitamin D and omega-3 fatty acids.
“With many nutrients, there is an optimal range of intake and blood levels, and more is not necessarily better,” she added.
Most Prostate Cancers Found Early
More than 400 sites in the United States, Canada, and Puerto Rico participated in SELECT, which was coordinated by SWOG, a federally funded cancer research cooperative group. Doctors monitored the participants according to contemporary community standards of screening and biopsy. This ensured that, as in general practice, some men had PSA tests and others did not.
During the 7 years of the trial (5.5 years of taking supplements and 1.5 years of not taking them), doctors diagnosed 65 cases of prostate cancer for every 1,000 men in the placebo group. In comparison, doctors diagnosed 76 cases for every 1,000 men in the vitamin E-only group.
Studies like SELECT make us realize that any pharmaceutical agent we give has the potential for benefit and for harm. That's why we engage in these large-scale randomized studies, especially for agents that are in widespread use.
—Dr. J. Michael Gaziano
Most of the detected cancers were found early, and therefore “the risk of a man dying from the disease is not very great,” said co-author Dr. Ian Thompson of the University of Texas Health Science Center at San Antonio.
He pointed out, however, that most men diagnosed with prostate cancer in the United States end up being treated with surgery or radiation, which can impair a man’s sexual and urinary functions.
“If a man is taking vitamin E, he should either stop taking it or talk to his doctor about a reason he should take it,” Dr. Thompson said. “And I can’t think of a reason he should take it.”
It is not clear why SELECT showed an increased risk for prostate cancer when earlier studies that led to the randomized trial showed that vitamin E protected against the disease. The study populations were different, however, and the original results may have been chance findings, the researchers said.
In fact, the prospective randomized trial, the gold standard in medical evidence, was launched precisely because the earlier studies were not definitive and needed to be confirmed.
The SELECT investigators have biological samples from the participants, and they intend to explore questions raised by the trial. For instance, men who took both supplements did not have an increased cancer risk, so there may have been an interaction between selenium and vitamin E.
The current results are an example of “rigorous scientific exploration,” noted Dr. Howard Parnes of NCI’s Division of Cancer Prevention, another co-author. “The idea of science is to put your observations to the test and see if they are correct,” he said. “You often learn the most from the studies that overturn conventional wisdom.”
Deadline Extended for Research Proposals Using SELECT and PCPT Samples
With the publication of new data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) that show an increased risk of prostate cancer in men taking vitamin E, the deadline for proposals to use biorepository samples from the study has been extended. SWOG, formerly known as the Southwest Oncology Group, is making resources from SELECT and the Prostate Cancer Prevention Trial (PCPT) available to the wider research community for the development of novel translational research projects, including those that might help decipher the role of vitamin E in prostate cancer.
Researchers interested in using samples from SELECT or PCPT must submit a letter of intent to SWOG by 5:00 p.m. ET on November 14, 2011. Full applications are due by 5:00 p.m. ET on December 15, 2011. SWOG will review proposals in January 2012 and send notifications in April 2012.
Together, SELECT and PCPT randomly assigned more than 53,000 men without prostate cancer to intervention or placebo, generating substantial clinical data related to the risk of developing prostate cancer, as well as corresponding biorepositories for molecular, epidemiologic, and other studies.
This article is part of a series of stories related to cancer advocacy. You can read more articles in the series here.
After DES: Tracking the Harms of a Prenatal Drug Exposure
This ad was placed by a drug maker in a major medical journal in 1957. It urges doctors to prescribe DES to all pregnant women. (Image courtesy of DES Action)
Kari Christianson was 23 years old when she first heard of a drug called diethylstilbestrol, or DES. It was the spring of 1972, and Dr. Arthur Herbst was on television discussing concerns about the drug. For decades, doctors had prescribed DES to millions of healthy pregnant women, including Christianson’s mother, based on unsubstantiated claims that it reduced the complications of pregnancy.
Dr. Herbst had recently published a study suggesting that the drug, when used by pregnant women, might cause cancer in their offspring years later. He had identified a group of young women who had a rare vaginal cancer typically seen only in older women. With the help of some astute mothers, he had confirmed that these women had been exposed to DES in the womb (in utero).
Christianson knew that her mother, after three miscarriages, had taken a drug while pregnant. And as she watched Dr. Herbst’s television interview, she realized that the drug must have been DES, the first synthetic form of estrogen. She wondered if this could explain her history of severe menstrual problems or a polyp that doctors had removed from her cervix.
When doctors at the Mayo Clinic in Rochester, MN, evaluated her a week later, they did not find cancer. But Christianson was never able to become pregnant. “It was a sobering experience,” she said recently. “I was fortunate, though, to have support from people in the health care system who were experts and knew what I was going through.”
Estimating the Health Risks of Exposed Daughters
On a return trip to the Mayo Clinic, Christianson joined a clinical study to track the health of women who had been exposed to DES in the womb. The results of this and two other studies have now been summarized in a single report documenting the range of long-term health problems associated with in utero exposure to DES.
“The toll of health problems caused by giving this drug to healthy women is unprecedented,” said the study’s lead author, Dr. Robert Hoover of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “And the longer we follow these women, the more we seem to find.”
In the October 6 New England Journal of Medicine (NEJM), Dr. Hoover and his colleagues estimated the absolute risks of 12 health outcomes associated with prenatal exposure to DES, including certain cancers and reproductive problems such as infertility, ectopic pregnancies, and preterm births.
Exposed daughters, for instance, have twice the risk of infertility and five times the risk of having a preterm delivery than unexposed women. Exposed women also have a slightly increased risk of breast cancer after age 40. (See a complete list of risks here.)
In contrast to what is now known about the health risks of DES, pharmaceutical companies marketed the drug as a way to prevent complications of pregnancy, such as miscarriage, though there was little evidence to support such claims. In fact, by 1953, a clinical trial had demonstrated that DES was not effective for these purposes, though doctors continued to prescribe the drug for almost two more decades.
Then, in April of 1971, Dr. Herbst published his landmark study linking DES to clear cell adenocarcinoma of the vagina in exposed daughters. Later that year, the U.S. Food and Drug Administration advised physicians that DES should not be prescribed to pregnant women.
“DES is a cautionary tale about not using drugs during pregnancy unless they are absolutely necessary,” said Dr. Elizabeth Hatch of the Boston University School of Public Health, a co-author of the current study.
Enormous Health Care Costs
As the authors of a recent editorial on DES in NEJM wrote, “The enormous health care costs for this cohort and the disruptions of their lives cannot be fully measured; in some cases, these effects have been devastating.”
Susan Helmrich is one such case. Exposed to DES in the womb, Helmrich was 21 years old when doctors found two malignant tumors in her vagina. During a 10.5-hour operation, surgeons removed most of her reproductive organs and reconstructed her vagina using tissue from her colon.
She has since survived two other rare cancers. Whether these were related to DES, she will probably never know. “There’s not a doctor or epidemiologist who would say that these cancers were related to my exposure to DES because no studies have been able to really look at these questions adequately,” said Helmrich, who herself is an epidemiologist and works as a wellness coach in Berkeley, CA.
DES is a cautionary tale about not using drugs during pregnancy unless they are absolutely necessary.
—Dr. Elizabeth Hatch
With data on more than 6,500 women (4,600 exposed and 1,900 unexposed), the current study “represents the culmination of years of work,” noted Helmrich, a longtime advocate for DES research.
In the late 1980s, Dr. Hoover and his colleagues combined three existing studies, or cohorts. This provided sufficient statistical power “to draw some legitimate conclusions about DES exposures,” said Dr. Herbst, who spent most of his career at the University of Chicago and is a co-author.
The new findings will help distinguish actual risks associated with DES exposure from unrelated risks, Dr. Herbst noted. Many anecdotal reports of risks caused by DES exposures have appeared over the years.
One challenge in documenting the full public health impact has been the lack of information on the total number of women who were exposed to DES. This information could affect estimates of the global burden of DES, but it will never be known, according to Dr. Annekathryn Goodman of Harvard Medical School.
The current study “is important and as good as it gets in terms of describing the burden of disease for this population many years after the initial exposures,” said Dr. Goodman, who was not involved in the study but co-wrote the recent NEJM editorial on DES.
Margaret Braun, author of DES Stories and an advocate for DES research, added: “This study came about because of the courage of profoundly traumatized people who were willing to talk about their experiences. We also needed the extraordinary persistence and expertise of these investigators to make the information concrete.”
Kari Christianson (center), pictured in 1973 with her husband and grandmother, suffered from infertility and other health problems.
DES as a Research Catalyst
Among other findings, the research shows that exposed daughters have twice the risk of early menopause compared with unexposed women. When early menopause occurs in exposed women, Dr. Hatch explained, it is another indication that a woman’s reproductive tract was damaged as the result of a prenatal exposure to DES some 40 to 50 years earlier.
“This is really remarkable,” she continued. “It makes one wonder whether other chemicals [in drugs] or in the environment might also be crossing the placenta and causing health effects years later.”
DES is an endocrine disrupter, a chemical that alters hormonal balance. The drug has become a research catalyst for investigating potentially similar effects of other chemical and environmental exposures that affect the endocrine system. Identifying these exposures is a challenge, however, particularly if the harmful health effects of an exposure in utero are not seen for decades.
“The potentially harmful effects of chemicals, including endocrine-disrupting chemicals, won’t always be as detectable as DES was,” said co-author Dr. Linda Titus-Ernstoff of Dartmouth Medical School. The rare vaginal cancers, she noted, were “a red flag” that sparked further investigations of exposed women.
We have more to learn from this experience. We're not done living yet, and as long as there are opportunities to study us, we want the research to continue.
—Kari Christianson, DES research advocate
Dr. Hoover pointed out that, if the vaginal cancers had not occurred, the more common side effects such as infertility and miscarriage would never have been linked to DES because these conditions are common in the general population.
The lessons learned from DES underscore the need for systematic long-term surveillance of drugs after they reach the market, he added.
Dr. Hoover and his colleagues are also studying sons exposed to DES in utero. These men have a higher risk of malformations in the genital tract than unexposed men.
The researchers have also begun to collect information on the granddaughters of exposed mothers. This work was sparked by animal models and subsequent studies in humans suggesting that DES exposure may alter genes in a way that persists into a third generation.
As for the exposed daughters, whether they will experience more health problems as they age remains to be seen. But the researchers intend to continue following them.
“We have more to learn from this experience,” said Christianson, who has been an advocate for DES research. “We’re not done living yet, and as long as there are opportunities to study us, we want the research to continue.”
As an invited lecturer in epidemiology, Dr. Robert Hoover has been asking students at medical schools the same question for 40 years: Have you heard of DES? Throughout the 1970s and into the 1980s, every hand in the room went up. But in the last 15 years, not a single student has heard of DES. Awareness of this public health disaster has declined.
By the late 1980s, grant support for long-running cohort studies of women exposed to DES had run out. To keep the studies active into the future, Dr. Hoover and the leaders of these cohorts came together in 1992 to form the NCI-sponsored DES Follow-up Study. Advocates for DES research played a critical role in helping to secure funding for this work and serving as advisors on the study steering committee.
By combining the cohorts, the researchers immediately had enough statistical power to rapidly uncover new health risks associated with prenatal exposure to DES. With the long-term follow-up offered by the combined study, they were also able to identify previously unrecognized effects and solidify the risks for some already established outcomes. This body of work, which is summarized in a new study, sparked interest in new research on chemical exposures that go beyond DES.
“The new study is quite an accomplishment,” wrote DES research advocate Margaret Braun in an e-mail. “It shows the need for decades-long research because exposed populations may show injuries over time. It is also a tribute to persistence. The NCI investigators have worked meticulously to gather information on DES health outcomes.”
Featured Clinical Trial
Bortezomib and Chemotherapy for Systemic Light-Chain Amyloidosis
Name of the Trial
Phase III Randomized Study of Melphalan and Dexamethasone with Versus without Bortezomib in Patients with Previously Untreated Systemic Light-Chain Amyloidosis (ECOG-E4A08). See the protocol summary.
Dr. Angela Dispenzieri
Dr. Angela Dispenzieri, Eastern Cooperative Oncology Group
Why This Trial Is Important Systemicamyloidosis refers to a group of diseases in which certain proteins fold into an abnormal conformation known as “amyloid.” The build-up of these abnormally folded proteins in organs and/or tissues can cause serious health problems.
The most common form of systemic amyloidosis in the United States is amyloid light-chain, or AL, amyloidosis. It is a rare disease in which abnormal plasma cells produce an abundance of improperly folded immunoglobulin (Ig) light-chain proteins. These misfolded Ig proteins accumulate in organs throughout the body and may impair organ function, ultimately leading to organ failure. Without treatment, patients diagnosed with AL amyloidosis typically die from organ failure within a year.
AL amyloidosis treatment focuses on the killing of plasma cells to reduce the production of misfolded Ig light-chain proteins. In patients who can tolerate it, high-dose chemotherapy with melphalan followed by transplantation of stem cells from the patient’s own blood (autologous stem cell transplantation) is one treatment option. In a phase II trial, this therapy reduced the number of misfolded light chains in the blood in 64 percent of patients. Such a hematologic response in patients with AL amyloidosis has been shown to predict longer survival. Unfortunately, about two-thirds of patients with this disease are unable to tolerate autologous stem cell transplantation because of advanced age and/or poor organ function caused by their disease or other health problems.
Patients who are ineligible for or who are concerned about the risk and logistics of autologous stem cell transplantation are usually treated with combination chemotherapy consisting of melphalan and a steroid, such as dexamethasone. However, only about two-thirds of the patients treated with melphalan and dexamethasone achieve a hematologic response, so new treatments are needed for patients with AL amyloidosis.
AL amyloidosis is related to a cancer of plasma cells called multiple myeloma. Adding the drug bortezomib to chemotherapy for multiple myeloma has helped improve survival in patients with that disease. The improvements seen in myeloma patients have spurred an interest in evaluating bortezomib in combination with chemotherapy for AL amyloidosis. In an early clinical trial, patients with relapsed AL amyloidosis experienced encouraging hematologic response rates when treated with bortezomib alone.
In the current clinical trial, patients with previously untreated AL amyloidosis will be randomly assigned to receive melphalan and dexamethasone with or without bortezomib. Doctors will assess the overall hematologic response rates to these chemotherapy regimens, as well as organ responses (improvements in the function of affected organs). In addition, they will monitor patients for toxicity, progression-free survival, overall survival, and quality of life.
“In patients with myeloma, the triplet regimen of bortezomib, melphalan, and dexamethasone appears to be better than the doublet of melphalan and dexamethasone, so it may well be that the triplet will perform better in AL amyloidosis as well,” said Dr. Dispenzieri.
“The caveat for AL patients, however, is that while drugs that work well in myeloma can also work well in AL patients, they tend to be a lot more toxic in these patients. So, even though the three-drug combination might turn out to be better at killing the plasma cells, patients might have so many more complications that they may not do any better, or may even do worse. We simply don’t know and that’s why we’re conducting the randomized trial,” she explained.
This article is part of a series of stories related to new technology in cancer research. You can read more articles in the series here.
Dr. Samuel Achilefu
Director of the Optical Radiology Laboratory and Professor of Radiology, Biochemistry & Molecular Biophysics, and Biomedical Engineering Washington University in St. Louis, MO
Dr. Samuel Achilefu
Growing up in Idah, Nigeria, a small city on the Niger River, Dr. Samuel Achilefu was advised by his parents that the best way to make a difference in the world is to pursue higher education. And, as a young boy, he was inclined toward the nuts-and-bolts side of science.
“I was always curious about how things worked, and I enjoyed mathematics and statistics,” he recounted recently. “For a time, I thought that solving equations could solve all the problems of the world. It wasn’t until I took chemistry and biology in college that I realized that to have an opportunity to make a real difference to people, you need to get into the laboratory.”
Today, Dr. Achilefu runs a 35-person research laboratory dedicated to pushing the boundaries of optical imaging to meet the requirements of modern molecular medicine. Optical imaging can be broadly defined as the use of light to visualize an object. A simple light microscope, the staple tool of high school biology classes, is an example of an optical imaging technique. So is a modern digital imaging system that can detect a fluorescent probe attached to a single cell—or even a single molecule within that cell.
Even with the widespread availability of nonoptical technologies such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) in hospitals and laboratories, researchers remain interested in improving optical imaging technology for three main reasons. First, the equipment required is relatively inexpensive. Second, optical techniques use no ionizing radiation. (Radiation exposure from medical imaging has become a concern.) And finally, optical imaging provides exquisite resolution. Powerful optical cameras can capture the presence of a molecule at extremely low concentrations, down to one trillionth of a mole (a unit of measurement used in chemistry to express the amounts of a chemical substance).
Until recently, the unfortunate trade-off for this resolution has been very limited depth. Traditional optical techniques can penetrate only about a few micrometers into living tissue. After that, the light waves start to scatter, producing an unreadable picture. Dr. Achilefu and his team at Washington University's Optical Radiology Laboratory are exploring new ways of breaking that depth barrier so that optical imaging can have a larger role in cancer diagnosis and treatment.
From Academia to Industry—and Back
After completing his initial training at the University of Ibadan, Nigeria’s premier university, in 1987 Dr. Achilefu received one of five prestigious French government scholarships issued to promising young students from Nigeria. He chose to study materials chemistry and biochemistry and earned his doctoral degree at the University of Nancy in France. Next, he went to Oxford University to do postdoctoral research on how oxygen is transported through the body in the bloodstream and on the development of blood substitutes.
He had initially hoped to stay on a straight career path in academia. Instead, he ended up on a nearly decade-long detour into industry. At the end of his postdoctoral work at Oxford, his mentor was recruited to lead a new research department at Mallinckrodt Medical, Inc., headquartered in St. Louis, MO, and he convinced Dr. Achilefu to come with him.
“My tenure there was very advantageous,” said Dr. Achilefu. “Companies are more interested in patents, not necessarily scientific publications like in academia, and the patent process taught me to always ask a simple question: ‘So what? After you’ve done whatever you want to do in the lab, what will be the impact on the people you’re trying to help?’ I got used to always thinking about the direct impact of whatever research I do.”
At Mallinckrodt, Dr. Achilefu continued to work on oxygen transport, developing systems to help deliver oxygen to the lungs of newborns with respiratory distress syndrome. The efficiency with which the molecule hemoglobin delivers oxygen throughout the body made him wonder if the delivery of molecules on the molecular level could be used to image biological processes in the body.
“In the 1980s, there was no such thing as molecular imaging as we know it today,” he remembered, “but people were thinking about it; there was a wave of curiosity. Then the first peptide-based targeting agent was approved by the FDA in the early 1990s to detect neuroendocrine tumors.” That compound, called OctreoScan, used a radionuclide, exposing patients to a small amount of radioactivity during testing. “I wanted to know if we could do the same thing without using ionizing radiation. That curiosity was what led me into optical molecular imaging,” he explained.
Near-Infrared Probes See Further
In 2001, with almost a decade of experience in optical imaging research, Dr. Achilefu returned to academia at the Washington University School of Medicine. In 10 years, he has expanded the Optical Radiology Laboratory from one full-time researcher—himself—to a 35-person multidisciplinary team with expertise ranging from biomedical engineering and medical physics to chemistry, biochemistry, and immunology. “We really believe in multidisciplinary research, and that draws a lot of people here,” he said.
Their current focus in cancer research is on developing chemical and biological imaging probes that can be used to visualize their target with near-infrared light. Near-infrared light has a longer wavelength than visual light, allowing it to travel deeper into tissue. “The exciting thing we’re doing now is taking this technology into intraoperative procedures to identify tumor margins in places that surgeons would normally have a difficult time seeing with the naked eye,” he said.
Dr. Samuel Achilefu's laboratory has developed goggles that allow surgeons to identify near-infrared fluorescence in tumor tissue during surgery. They are refining this prototype to provide binocular vision.
His team has constructed a prototype goggle system that would allow a surgeon to identify near-infrared fluorescence in tumor tissue during surgery, without having to stop and look at images captured by a camera. The goggles also have the capacity to broadcast what the surgeon sees over the Internet in real time for telemedicine applications.
After receiving positive feedback from researchers around the world on their proof-of-concept study published last May in Surgery, the team is shrinking its prototype and refining the goggles to give surgeons binocular, three-dimensional vision, with the aim of testing it on human cancers.
In another, NCI-funded project, the team is pairing near-infrared probes with endoscopy. Their current probes can see about 2 cm into the body—a depth that can provide useful anatomical information when used endoscopically or with a catheter in the gastrointestinal tract or cervix, for example. Between endoscopy and catheterization, “a significant percentage of procedures done in hospital[s] today are amenable to optical imaging,” explained Dr. Achilefu. He and his colleagues plan to test the new probe for improving the removal of polyps and small tumors in the colon during endoscopic surgery.
The team also has NCI funding to test whether photoacoustic-based multimodal imaging, which uses optical technology and sound to pinpoint cancer cells, could improve upon traditional sentinel lymph node biopsy for breast cancer. This project, in partnership with Dr. Lihong Wang, director of the Optical Imaging Laboratory at Washington University, is testing a near-infrared probe to see if tiny deposits of cancer cells in the axillary lymph nodes could be detected with imaging alone, eliminating the need for surgical removal of suspected sentinel nodes.
In the future, Dr. Achilefu and his team hope to use their probes to monitor cancer treatment at the molecular level—for example, to see within hours of administration whether a chemotherapy drug is reaching and affecting cancer cells. “Today, we have to wait for weeks or months, because we’re looking for structural changes [in the tumor]. We believe optical imaging would be able to provide that information within 24 hours, and that it will be predictive,” he proposed.
Dr. Achilefu remains as excited about the potential of optical technology as he did as a newly minted scientist, watching the birth of its use in molecular imaging. And he stays inspired by his students who feel the same way. “Young people are really excited about this technology, so that’s why I’m happy about the future of our optical imaging work,” he said.
With the aid of a planning grant from NCI, Purdue University established a University Cancer Research Committee in 1975. Three years later, the Purdue Center for Cancer Research was awarded an NCI Cancer Center Support Grant as a basic-science cancer center.
The center brings together 82 faculty members from 6 colleges and 16 departments across the university to share ideas, insights, and findings. More than 500 researchers, post-docs, and graduate and undergraduate students at Purdue University focus on cancer research.
The Center for Cancer Research links cutting-edge basic research, medicinal chemistry expertise, and engineering applications to further cancer research. Using the combined expertise of Purdue scientists, the center focuses on the discovery of biological processes, new technologies, and new chemical entities that lead to the development of innovative instrumentation, diagnostic tools, and novel cancer therapeutics.
The Purdue University Center for Cancer Research has four programs. Investigators in the Cell Identity and Signaling Program study the key molecules and processes that distinguish a cancer cell from a normal cell, whereas researchers in the Chemical and Structural Biology Program study the underlying mechanisms involved in cancer, identify biological targets for cancer chemotherapy, and develop potential chemical approaches to cancer treatment. The Medicinal Chemistry Program uses chemical, biochemical, cellular, and animal models to design and discover cancer drugs. And researchers in the Drug Delivery and Molecular Sensing Program bring together engineering and chemistry to improve drug delivery, imaging, and biomarker identification.
The center also has four Discovery Groups that focus on specific cancers: breast, prostate, bladder, and pancreatic. These groups conduct multidisciplinary studies on each disease.
The center coordinates a broad spectrum of collaborative research and fosters the application of new discoveries to cancer care. For example, the discovery of folate receptors, uniquely expressed molecules on the surface of cancer cells, led to the development of a new approach for treating cancer: targeted delivery of therapeutic drugs and imaging agents.
The drug discovery process within the Center for Cancer Research starts at the cellular level and ends with a viable human therapy that can reduce cancer morbidity and mortality. The center is enhancing its portfolio of novel and innovative drug candidates to treat cancer.
The center's research is also improving the understanding of drug targets for future drug therapies and detection technology that will aid clinicians in early diagnosis or monitoring of cancer therapies.
Collectively, the center's researchers will use their scientific expertise and collaborations to discover solutions through drug design and delivery, detection technology, and target development for drug discovery.
Other Notable Programs
Purdue University Center for Cancer Research's Oncological Sciences Center (OSC) blends basic cancer research and engineering research to cultivate and support innovative, multi-investigator, interdisciplinary research teams comprised of Center for Cancer Research members and nonmembers hoping to initiate cancer-related research projects. The OSC provides an environment for cross-fertilization of ideas among faculty members in disparate disciplines; ideas from research fields outside biology and medicine may provide novel solutions to current research and development problems.
Public Comment Sought on Draft Prostate Cancer Screening Recommendation
The draft recommendation was based on a review of findings from clinical trials of prostate cancer screening and clinical trials and cohort studies of treatment for prostate cancers diagnosed primarily on the basis of PSA screening. The recommendation does not cover PSA testing as part of “a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer,” the Task Force wrote, or “the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.”
A public comment period on the draft recommendation is open until November 8. Comments should address the draft recommendation “and how the [USPSTF] decisions are communicated,” the Task Force explained.
Comments may be submitted via the USPSTF website or via mail to Dr. Robert Cosby, c/o USPSTF, 540 Gaither Road, Rockville, MD 20850.
Public Comment Sought on Updated Cervical Cancer Screening Recommendations
On October 18, the U.S. Preventive Services Task Force (USPSTF) issued draft recommendations on screening for cervical cancer. The recommendations are an update of previous task force recommendations and are open for a 30-day public comment period.
The draft recommendations advise that screening with the Pap test should be done every 3 years for women ages 21 to 65 who have had vaginal intercourse and have a cervix. In women younger than age 30, the recommendations advise against screening using human papillomavirus (HPV) testing, either alone or in combination with the Pap test. In women 30 years of age and older, the task force concluded, “the current evidence is insufficient to assess the balance of benefits and harms of HPV testing, alone or in combination with [a Pap test].”
The public comment period on the draft recommendation is open until November 16. Comments may be submitted via the USPSTF website or via mail to Dr. Robert Cosby, c/o USPSTF, 540 Gaither Road, Rockville, MD 20850.
NCI Recognizes Community Physician J. Philip Kuebler
Dr. J. Philip Kuebler
The 2011 Harry Hynes Award, which recognizes excellence in research within the Community Clinical Oncology Program (CCOP) Network, has been awarded to Dr. J. Philip Kuebler, the principal investigator of the Columbus CCOP, in Columbus, OH.
Dr. Kuebler has been the principal investigator for the Columbus CCOP since 1998 and active in clinical trials research for more than 30 years. He has served as a protocol coordinator for a large adjuvant colon cancer treatment trial and represented community-based medical oncologists on the NCI Gastrointestinal Cancer Steering Committee and the Cancer and Leukemia Group B Data and Safety Monitoring Board.
The CCOP program established the Harry Hynes Award in 2001 to recognize and acknowledge outstanding commitment by community investigators to clinical research. The award was named for Dr. Harry Hynes, the principal investigator of the Wichita Community Clinical Oncology Program, for his tremendous dedication and commitment to bringing clinical trials to the community setting.
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