Scientists searching for the source of aggressive and deadly breast cancers may have been looking in the wrong place, new research suggests.
The findings, which shed light on how the most dangerous breast cancers grow, could lead to new treatments and prevention strategies.
Tumours arise in two types of glandular tissue in the breast, the outer "basal" cells and inner "luminal" cells.
Previously it was thought that more aggressive cancers sprung from basal stem cells. Milder forms of cancer were believed to arise from "intermediate" luminal cells.
The vast majority of inherited breast tumours with defective BRCA1 genes - one of the most aggressive types - have basal-like characteristics.
But scientists who conducted studies on mice to confirm the origin of BRCA1 cancer tumours found that looks can be deceptive.
The researchers deleted the BRCA1 gene in both mouse basal stem cells and luminal intermediate cells.
Tumours formed in both kinds of cell, but only luminal cells had features identical to human BRCA1 cancers. They also matched the majority of human basal-like "triple negative" cancers not associated with BRCA1 mutations.
Study leader Dr Matt Smalley, from the charity Breakthrough Breast Cancer, said: "These results represent a major advance in our understanding of breast cancer. It means we can now look very closely at where the disease forms and which genes are involved in that process.
"This knowledge will greatly improve the chance of finding effective new targeted treatments for breast cancer patients in the future."
Σάββατο 4 Σεπτεμβρίου 2010
ORAL BIPHOSPHONATES AND ESOPHAGEAL CANCER RISK
September 3 2010 — In an about face of findings, a new study reports that oral bisphosphonates — widely prescribed for osteoporosis — are associated with an increased risk for esophageal cancer. The study comes just weeks after another study, using the same database, found no such link.
The new case–control study found that the risk was statistically significant among patients who had 10 or more prescriptions for the drugs — compared with patients who had 1 to 9 prescriptions.
The relative risk also increases with duration of use; it doubles over about a 5-year period, according to the authors of the new study, led by Jane Green, PhD, a clinical epidemiologist from the Cancer Epidemiology Unit at the University of Oxford in the United Kingdom.
However, an expert in gastroesophageal cancer contacted by Medscape Medical News suggested that clinicians should not stop prescribing oral bisphosphonates.
Clinicians need to weigh the benefits of oral bisphosphonates such as the reduction in hip fracture against the risks such as the increase in esophageal cancer, said Gerard Blobe, MD, associate professor of medicine at Duke University School of Medicine in Durham, North Carolina.
"The absolute risk increase found in the study is still pretty small — 1 in 1000 to 2 in 1000 with about 5 years of use of oral bisphosphonates," he observed about the new data.
"I would say that, generally, the benefits outweigh the risks," he said.
Dr. Blobe also explained that oral bisphosphonates could theoretically cause esophageal cancer because "irritation" of the esophagus might "set the stage for cancer in some patients."
The new study's findings on oral bisphosphonates conflict with a recent British study that found no link.
Notably, both studies used the UK General Practice Research Database.
"What would cause these differences [in findings]?" asks an editorial that accompanies the new study, both of which were published online September 2 in BMJ.
A "major difference" in the 2 studies is the average length of follow-up, notes the editorialist, Diane Wysowski, PhD, an epidemiologist at the US Food and Drug Administration (FDA) in Silver Spring, Maryland. The earlier negative study had 4.5 years of follow-up; the new positive study has 7.7 years.
The positive study also had "an adequate sample size," said Dr. Wysowski.
Dr. Green and her coauthors said that their positive study had "greater statistical power" than the negative study — with 5 matched controls per case, compared with equal numbers in the exposed and comparison groups in negative study.
Even if oral bisphosphonates cause cancer, "the incidence of esophageal cancer in this population of users would be expected to remain relatively low," writes Dr. Wysowski.
Despite this comment, another gastroenterologist from Duke said that esophageal cancer is of growing concern in the United States and other industrialized countries.
"The incidence of esophageal adenocarcinoma is rising more rapidly than any other malignancy in the past 5 years in Western countries. The reasons are unknown," said Ivy Altomare, MD, assistant professor of medicine and a colleague of Dr. Blobe.
Advice to Patients
The immediate question for clinicians is what to tell patients, says Dr. Wysowski. Her primary recommendation is to tell patients to take the pills correctly. Dr. Blobe explained the reason for the recommendation.
As soon as it was recognized that oral bisphosphonates were associated with esophageal problems, the package inserts for these drugs were changed, he said. The change included directions on how to best take the drugs, and dictated that patients with a history of esophageal problems not be prescribed these agents.
After the package insert was changed, "the incidence of esophageal-related problems with the drugs subsequently dropped," he said. This chain of events suggests that noncompliant patients might be the ones who develop problems, he said.
Dr. Wysowski reminds clinicians to reinforce directions for drug usage with each prescription. Namely, remind patients to take oral bisphosphonates in the morning with a full glass of plain water on an empty stomach — at least 30 to 60 minutes before the first food, beverage, or medication.
Also tell patients not to recline for at least 30 to 60 minutes after taking an oral bisphosphonate.
The new study results might be, in an odd way, useful to clinicians, suggested Dr. Blobe. "This result could incentivize patients to take the pill correctly," he said.
Study Results
The 2 studies come out about a year and a half after the FDA reported 23 cases of esophageal cancer between 1995 and 2008 in patients using alendronate and another 31 cases in patients using a variety of bisphosphonates in Europe and Japan.
Dr. Wysowski was the author of that FDA report, which was published in January 2009 (N Engl J Med. 2009;360:89-90). That paper immediately prompted a couple of quick studies. However, those 2 studies had methods and data that were "sparse", notes Dr. Wysowski in her current editorial.
So that leaves the new positive study and the earlier negative study as the main objects of attention in the debate on this matter.
The 2 sets of investigators studied the problem in slightly different ways, points out Dr. Wysowski.
The negative study compared the incidence of esophageal cancer and gastric cancer in patients who were exposed or not exposed to oral bisphosphonates, and found no increase in the risk for either cancer. The positive study compared the frequency of oral bisphosphonate exposure in cases and matched noncases.
In their positive study, Dr. Green and her colleagues set out to test the hypothesis that risk for esophageal, but not gastric or colorectal, cancer is higher in users of oral bisphosphonates.
They used a UK General Practice Research Database cohort and identified men and women 40 years or older who were diagnosed from 1995 to 2005 — 2,954 with esophageal cancer, 2,018 with gastric cancer, and 10,641 with colorectal cancer. Five controls per case were matched for age, sex, general practice, and observation time.
After adjustment for smoking, alcohol, and body mass index, they examined the relative risks for the 3 different cancers.
They found that the incidence of esophageal cancer was higher in cases with 1 or more previous prescriptions for oral bisphosphonates than in those with no such prescriptions (relative risk [RR], 1.30; 95% confidence interval [CI], 1.02 - 1.66; P = .02).
As noted above, the risk for esophageal cancer was significantly higher after 10 or more prescriptions (RR, 1.93; 95% CI, 1.37 - 2.70) than after 1 to 9 (RR, 0.93; 95% CI, 0.66 - 1.31; P for heterogeneity = .002), and for use for more than 3 years (RR vs no prescription, 2.24; 95% CI, 1.47 - 3.43).
This doubling of risk in longer-term users (i.e., over 3 years; the average length of use was about 5 years) is where most of the risk is with bisphosphonates, according to the data. The relative risks for people who used oral bisphosphonates for less than a year or for 1 to 3 years were about 1 for both — in other words, they had no increased risk.
Cancers of the stomach and colorectum were not associated with oral bisphosphonates, the authors reported.
The authors have disclosed no relevant financial relationships.
BMJ. 2010; 341:c4444, c4506.
The new case–control study found that the risk was statistically significant among patients who had 10 or more prescriptions for the drugs — compared with patients who had 1 to 9 prescriptions.
The relative risk also increases with duration of use; it doubles over about a 5-year period, according to the authors of the new study, led by Jane Green, PhD, a clinical epidemiologist from the Cancer Epidemiology Unit at the University of Oxford in the United Kingdom.
However, an expert in gastroesophageal cancer contacted by Medscape Medical News suggested that clinicians should not stop prescribing oral bisphosphonates.
Clinicians need to weigh the benefits of oral bisphosphonates such as the reduction in hip fracture against the risks such as the increase in esophageal cancer, said Gerard Blobe, MD, associate professor of medicine at Duke University School of Medicine in Durham, North Carolina.
"The absolute risk increase found in the study is still pretty small — 1 in 1000 to 2 in 1000 with about 5 years of use of oral bisphosphonates," he observed about the new data.
"I would say that, generally, the benefits outweigh the risks," he said.
Dr. Blobe also explained that oral bisphosphonates could theoretically cause esophageal cancer because "irritation" of the esophagus might "set the stage for cancer in some patients."
The new study's findings on oral bisphosphonates conflict with a recent British study that found no link.
Notably, both studies used the UK General Practice Research Database.
"What would cause these differences [in findings]?" asks an editorial that accompanies the new study, both of which were published online September 2 in BMJ.
A "major difference" in the 2 studies is the average length of follow-up, notes the editorialist, Diane Wysowski, PhD, an epidemiologist at the US Food and Drug Administration (FDA) in Silver Spring, Maryland. The earlier negative study had 4.5 years of follow-up; the new positive study has 7.7 years.
The positive study also had "an adequate sample size," said Dr. Wysowski.
Dr. Green and her coauthors said that their positive study had "greater statistical power" than the negative study — with 5 matched controls per case, compared with equal numbers in the exposed and comparison groups in negative study.
Even if oral bisphosphonates cause cancer, "the incidence of esophageal cancer in this population of users would be expected to remain relatively low," writes Dr. Wysowski.
Despite this comment, another gastroenterologist from Duke said that esophageal cancer is of growing concern in the United States and other industrialized countries.
"The incidence of esophageal adenocarcinoma is rising more rapidly than any other malignancy in the past 5 years in Western countries. The reasons are unknown," said Ivy Altomare, MD, assistant professor of medicine and a colleague of Dr. Blobe.
Advice to Patients
The immediate question for clinicians is what to tell patients, says Dr. Wysowski. Her primary recommendation is to tell patients to take the pills correctly. Dr. Blobe explained the reason for the recommendation.
As soon as it was recognized that oral bisphosphonates were associated with esophageal problems, the package inserts for these drugs were changed, he said. The change included directions on how to best take the drugs, and dictated that patients with a history of esophageal problems not be prescribed these agents.
After the package insert was changed, "the incidence of esophageal-related problems with the drugs subsequently dropped," he said. This chain of events suggests that noncompliant patients might be the ones who develop problems, he said.
Dr. Wysowski reminds clinicians to reinforce directions for drug usage with each prescription. Namely, remind patients to take oral bisphosphonates in the morning with a full glass of plain water on an empty stomach — at least 30 to 60 minutes before the first food, beverage, or medication.
Also tell patients not to recline for at least 30 to 60 minutes after taking an oral bisphosphonate.
The new study results might be, in an odd way, useful to clinicians, suggested Dr. Blobe. "This result could incentivize patients to take the pill correctly," he said.
Study Results
The 2 studies come out about a year and a half after the FDA reported 23 cases of esophageal cancer between 1995 and 2008 in patients using alendronate and another 31 cases in patients using a variety of bisphosphonates in Europe and Japan.
Dr. Wysowski was the author of that FDA report, which was published in January 2009 (N Engl J Med. 2009;360:89-90). That paper immediately prompted a couple of quick studies. However, those 2 studies had methods and data that were "sparse", notes Dr. Wysowski in her current editorial.
So that leaves the new positive study and the earlier negative study as the main objects of attention in the debate on this matter.
The 2 sets of investigators studied the problem in slightly different ways, points out Dr. Wysowski.
The negative study compared the incidence of esophageal cancer and gastric cancer in patients who were exposed or not exposed to oral bisphosphonates, and found no increase in the risk for either cancer. The positive study compared the frequency of oral bisphosphonate exposure in cases and matched noncases.
In their positive study, Dr. Green and her colleagues set out to test the hypothesis that risk for esophageal, but not gastric or colorectal, cancer is higher in users of oral bisphosphonates.
They used a UK General Practice Research Database cohort and identified men and women 40 years or older who were diagnosed from 1995 to 2005 — 2,954 with esophageal cancer, 2,018 with gastric cancer, and 10,641 with colorectal cancer. Five controls per case were matched for age, sex, general practice, and observation time.
After adjustment for smoking, alcohol, and body mass index, they examined the relative risks for the 3 different cancers.
They found that the incidence of esophageal cancer was higher in cases with 1 or more previous prescriptions for oral bisphosphonates than in those with no such prescriptions (relative risk [RR], 1.30; 95% confidence interval [CI], 1.02 - 1.66; P = .02).
As noted above, the risk for esophageal cancer was significantly higher after 10 or more prescriptions (RR, 1.93; 95% CI, 1.37 - 2.70) than after 1 to 9 (RR, 0.93; 95% CI, 0.66 - 1.31; P for heterogeneity = .002), and for use for more than 3 years (RR vs no prescription, 2.24; 95% CI, 1.47 - 3.43).
This doubling of risk in longer-term users (i.e., over 3 years; the average length of use was about 5 years) is where most of the risk is with bisphosphonates, according to the data. The relative risks for people who used oral bisphosphonates for less than a year or for 1 to 3 years were about 1 for both — in other words, they had no increased risk.
Cancers of the stomach and colorectum were not associated with oral bisphosphonates, the authors reported.
The authors have disclosed no relevant financial relationships.
BMJ. 2010; 341:c4444, c4506.
19th CENTURY MEDICINE
NEW YORK (Reuters Health) Aug 30 - Finger length - specifically, the ratio of the second to fourth digits -- might be a predictor of prostate cancer risk, according to a recent study from Korea.
Men with a digit ratio below 0.95 had higher average prostate-specific antigen (PSA) levels and higher prostate cancer risks than men with larger ratios.
But the sample size was small (366 men) and the results, which appeared online July 13th in BJU International, must be interpreted with caution and confirmed, experts warn.
Lead author Dr. Han Jung and his colleagues from the Gachon University Gil Hospital in Incheon, Korea, measured the second to fourth digit ratio (using digital vernier calipers), prostate volume, and PSA and testosterone levels in men age 40 and older with lower urinary tract symptoms. Those with PSA levels of 3 ng/mL or more had prostate biopsies.
Out of the 366 patients, 89 had PSA levels high enough to warrant a biopsy, and 28 of those were diagnosed with prostate cancer. There was no relationship between digit ratio and prostate volume, but lower digit ratios were associated with higher PSA levels (r = -0.140, P = 0.007).
When patients were divided into groups, one with digit ratios below 0.95 and the other with ratios equal to or above 0.95, the lower ratio group had higher mean PSA levels (3.26 vs. 1.89 ng/mL) and a higher overall rate of prostate cancer (11.4% vs. 3.8%) than the higher ratio group. There was no difference in age, testosterone level, or prostate volume between the two groups.
The results suggest that prenatal androgen exposure, known to be negatively associated with digit ratios, may predict PSA levels and prostate cancer risk, the authors say. Prenatal androgen exposure in black people, who have been shown to have lower digit ratios on average than white people, could help explain why black men are 2.5 times more likely to die of prostate cancer than white men, they add.
Dr. John Manning, a psychologist at Swansea University in Wales who is an expert on digit ratios, praised the study's authors for measuring digit lengths directly with calipers, instead of through photocopies, which can produce inaccurate readings, he said. Although he has also suggested a possible link between prenatal testosterone and prostate cancer risk, he cautioned against reading too much into the findings.
"This is only one study with a relatively small sample," he told Reuters Health by email. "We need to see it repeated with larger samples and in other ethnic groups."
Even if the finding is confirmed, it would only reflect average trends across a population, and shouldn't be used to assess an individual's risk of prostate cancer, according to Dr. Marc Breedlove, a neuroscientist at Michigan State University.
"If digit ratios correlate with prostate cancer risk, that does indeed indicate that individual differences in exposure to androgens early in life affect the likelihood of prostate cancer in adulthood," Dr. Breedlove told Reuters Health by email. "But I very much doubt whether that correlation could be used to accurately predict the probability that a particular person will or will not contract prostate cancer."
BJU Int. Posted online July 13, 2010. Abstract
Men with a digit ratio below 0.95 had higher average prostate-specific antigen (PSA) levels and higher prostate cancer risks than men with larger ratios.
But the sample size was small (366 men) and the results, which appeared online July 13th in BJU International, must be interpreted with caution and confirmed, experts warn.
Lead author Dr. Han Jung and his colleagues from the Gachon University Gil Hospital in Incheon, Korea, measured the second to fourth digit ratio (using digital vernier calipers), prostate volume, and PSA and testosterone levels in men age 40 and older with lower urinary tract symptoms. Those with PSA levels of 3 ng/mL or more had prostate biopsies.
Out of the 366 patients, 89 had PSA levels high enough to warrant a biopsy, and 28 of those were diagnosed with prostate cancer. There was no relationship between digit ratio and prostate volume, but lower digit ratios were associated with higher PSA levels (r = -0.140, P = 0.007).
When patients were divided into groups, one with digit ratios below 0.95 and the other with ratios equal to or above 0.95, the lower ratio group had higher mean PSA levels (3.26 vs. 1.89 ng/mL) and a higher overall rate of prostate cancer (11.4% vs. 3.8%) than the higher ratio group. There was no difference in age, testosterone level, or prostate volume between the two groups.
The results suggest that prenatal androgen exposure, known to be negatively associated with digit ratios, may predict PSA levels and prostate cancer risk, the authors say. Prenatal androgen exposure in black people, who have been shown to have lower digit ratios on average than white people, could help explain why black men are 2.5 times more likely to die of prostate cancer than white men, they add.
Dr. John Manning, a psychologist at Swansea University in Wales who is an expert on digit ratios, praised the study's authors for measuring digit lengths directly with calipers, instead of through photocopies, which can produce inaccurate readings, he said. Although he has also suggested a possible link between prenatal testosterone and prostate cancer risk, he cautioned against reading too much into the findings.
"This is only one study with a relatively small sample," he told Reuters Health by email. "We need to see it repeated with larger samples and in other ethnic groups."
Even if the finding is confirmed, it would only reflect average trends across a population, and shouldn't be used to assess an individual's risk of prostate cancer, according to Dr. Marc Breedlove, a neuroscientist at Michigan State University.
"If digit ratios correlate with prostate cancer risk, that does indeed indicate that individual differences in exposure to androgens early in life affect the likelihood of prostate cancer in adulthood," Dr. Breedlove told Reuters Health by email. "But I very much doubt whether that correlation could be used to accurately predict the probability that a particular person will or will not contract prostate cancer."
BJU Int. Posted online July 13, 2010. Abstract
FAMILY HISTORY AND PROSTATE CANCER RISK
August 30, 2010 — Increased diagnostic activity among men who have a brother with prostate cancer appears to contribute to their increased risk for prostate cancer, say Swedish researchers.
The incidence of prostate cancer was higher among brothers of index patients than among men of the same age in the general Swedish population (standardized incidence ratio [SIR], 3.1; 95% confidence interval [CI], 2.9 - 3.3).
However, this 3-fold increased incidence was accompanied by increased diagnostic activity, the researchers report.
This increased diagnostic activity will "inflate" family history as a risk factor, say the authors, led by Ola Bratt, MD, from Helsingborg Hospital in Sweden. Their findings were published online August 19 in the Journal of the National Cancer Institute.
To dramatically illustrate their point, the authors highlighted cases in which 2 brothers in a family had been diagnosed with prostate cancer.
The risk was "very high" that a third brother would also be diagnosed with prostate cancer, particularly a T1c tumor (which is prostate-specific antigen [PSA]-detected by definition), within the first year after the second brother's diagnosis (SIR, 22; 95% CI, 15 - 31).
"This result must not be interpreted as meaning that men with 2 brothers with prostate cancer have a 22-fold increased risk of developing symptomatic prostate cancer, compared with the general population," the authors write. "But rather that such men are very likely to undergo PSA testing."
Notably, the researchers acknowledge that genetic factors are very important in prostate cancer.
"Hereditary factors may be more important in the etiology of prostate cancer than of any other cancer," they write, citing a study of twins (N Engl J Med. 2000;343:78-85).
However, there is no biomarker that indicates a genetic predisposition to clinically consequential prostate cancer.
Thus, the authors want clinicians to know that, when counseling men with prostate cancer in the family, "familial aggregation of prostate cancer may be at least partially caused by increased diagnostic activity."
In an editorial that accompanies the study, a trio of experts suggest that the only way to circumvent such bias is to find new ways to evaluate prostate cancer.
"Perhaps the best tactic would be to change our approach from seeking risk factors for prostate cancer (a disease that is ubiquitous, with many patients probably being better off if it were not detected by screening) to an assessment of factors related to biologically consequential prostate cancer (i.e., metastatic disease or prostate-cancer-specific death)," write editorialists Ian Thompson, MD, Donna P. Ankerst, PhD, and Catherine M. Tangen, DrPH.
They are all from the Cancer Therapy and Research Center of the University of Texas Health Science Center at San Antonio.
An "Entrenched" Risk, But How So?
In their editorial, Dr. Thompson and his colleagues say that the connection between family history and increased prostate risk is well established — and then some.
"That a family history of prostate cancer increases a man's risk of a diagnosis of this disease is now entrenched in the medical literature," the editorialists write.
Dr. Thompson, who is known for "rethinking" prostate cancer issues, and his colleagues explore when this entrenchment came to be.
They review published papers on the association between family history and prostate neoplasms.
In the 10 years from 1977 to 1986, there were 7 publications on the subject — a rate of 0.7 articles per year.
After 1986, there was an ongoing uptick in the published research.
From 1987 to 1996, there were 79 articles, a rate of 7.9 articles per year. From 1997 to 2006, there were 45.8 articles per year; and in the past 4 years or so, there were 65 articles per year.
"Why did it take us until the mid-1980s to fully recognize or explore adequately the familial association?" ask the editorialists.
They then answer their own question — somewhat.
"Certainly, the explosion in total numbers of prostate cancers has drawn our attention to the disease and provided the data to explore this association," they write, noting that the time of the research uptick — the mid-1980s — is the "PSA era," when widespread PSA testing began in the United States.
However, the editorialists also say that the study from Sweden provides "another explanation" for how the link between family history and prostate neoplasms came to be "entrenched" in the literature starting in the mid-1980s.
The Swedish study shows how, "in the PSA era, a man with a brother or father with prostate cancer was more likely to be screened for prostate cancer by PSA testing. Against the background of an enormous number of undiagnosed (but diagnosable) prostate cancers, this simple decision could lead to a prostate biopsy and exaggerate the link between family history and prostate cancer."
Findings
Their new findings are not entirely novel, admit Dr. Bratt and his coauthors.
Other researchers have found that there is an increased detection of prostate cancer shortly after a diagnosis of the disease in a family (J Natl Cancer Inst. 2005;97:1575-1579).
However, in their study, the Swedes added a few more details to what is understood about how PSA testing influences familial prostate cancer risk.
The study involved 22,511 brothers of 13,975 index patients with prostate cancer in the National Prostate Cancer Register of Sweden.
The investigators found, for the first time, that brothers of index patients who had a higher socioeconomic status (SIR, 4.2; 95% CI, 3.7 - 4.7) were more likely to be diagnosed with prostate cancer than brothers of index patients with a lower socioeconomic status (SIR, 2.8; 95% CI, 2.4 - 3.2).
The risk for T1c tumors (SIR, 3.4; 95% CI, 3.2 - 3.8), which are by definition diagnosed after a PSA test, was higher than for metastatic tumors (SIR, 2.0; 95% CI, 1.5 - 2.6), report the study authors.
And the risk for T1c tumors was highest during the first year after the diagnosis of the index patient (SIR, 4.3; 95% CI, 3.8 - 4.9), compared with the risk in the following years (SIR range, 2.8 to 3.3).
"The diagnostic activity among brothers of prostate cancer patients was especially high during the first year after a prostate cancer diagnosis in the family," the authors point out.
The study was funded by the Swedish Research Council, the Swedish Cancer Society, and Vasterbotten County Council. The authors have disclosed no relevant financial relationships.
J Natl Cancer Inst. Published online August 19, 2010. Abstract
The incidence of prostate cancer was higher among brothers of index patients than among men of the same age in the general Swedish population (standardized incidence ratio [SIR], 3.1; 95% confidence interval [CI], 2.9 - 3.3).
However, this 3-fold increased incidence was accompanied by increased diagnostic activity, the researchers report.
This increased diagnostic activity will "inflate" family history as a risk factor, say the authors, led by Ola Bratt, MD, from Helsingborg Hospital in Sweden. Their findings were published online August 19 in the Journal of the National Cancer Institute.
To dramatically illustrate their point, the authors highlighted cases in which 2 brothers in a family had been diagnosed with prostate cancer.
The risk was "very high" that a third brother would also be diagnosed with prostate cancer, particularly a T1c tumor (which is prostate-specific antigen [PSA]-detected by definition), within the first year after the second brother's diagnosis (SIR, 22; 95% CI, 15 - 31).
"This result must not be interpreted as meaning that men with 2 brothers with prostate cancer have a 22-fold increased risk of developing symptomatic prostate cancer, compared with the general population," the authors write. "But rather that such men are very likely to undergo PSA testing."
Notably, the researchers acknowledge that genetic factors are very important in prostate cancer.
"Hereditary factors may be more important in the etiology of prostate cancer than of any other cancer," they write, citing a study of twins (N Engl J Med. 2000;343:78-85).
However, there is no biomarker that indicates a genetic predisposition to clinically consequential prostate cancer.
Thus, the authors want clinicians to know that, when counseling men with prostate cancer in the family, "familial aggregation of prostate cancer may be at least partially caused by increased diagnostic activity."
In an editorial that accompanies the study, a trio of experts suggest that the only way to circumvent such bias is to find new ways to evaluate prostate cancer.
"Perhaps the best tactic would be to change our approach from seeking risk factors for prostate cancer (a disease that is ubiquitous, with many patients probably being better off if it were not detected by screening) to an assessment of factors related to biologically consequential prostate cancer (i.e., metastatic disease or prostate-cancer-specific death)," write editorialists Ian Thompson, MD, Donna P. Ankerst, PhD, and Catherine M. Tangen, DrPH.
They are all from the Cancer Therapy and Research Center of the University of Texas Health Science Center at San Antonio.
An "Entrenched" Risk, But How So?
In their editorial, Dr. Thompson and his colleagues say that the connection between family history and increased prostate risk is well established — and then some.
"That a family history of prostate cancer increases a man's risk of a diagnosis of this disease is now entrenched in the medical literature," the editorialists write.
Dr. Thompson, who is known for "rethinking" prostate cancer issues, and his colleagues explore when this entrenchment came to be.
They review published papers on the association between family history and prostate neoplasms.
In the 10 years from 1977 to 1986, there were 7 publications on the subject — a rate of 0.7 articles per year.
After 1986, there was an ongoing uptick in the published research.
From 1987 to 1996, there were 79 articles, a rate of 7.9 articles per year. From 1997 to 2006, there were 45.8 articles per year; and in the past 4 years or so, there were 65 articles per year.
"Why did it take us until the mid-1980s to fully recognize or explore adequately the familial association?" ask the editorialists.
They then answer their own question — somewhat.
"Certainly, the explosion in total numbers of prostate cancers has drawn our attention to the disease and provided the data to explore this association," they write, noting that the time of the research uptick — the mid-1980s — is the "PSA era," when widespread PSA testing began in the United States.
However, the editorialists also say that the study from Sweden provides "another explanation" for how the link between family history and prostate neoplasms came to be "entrenched" in the literature starting in the mid-1980s.
The Swedish study shows how, "in the PSA era, a man with a brother or father with prostate cancer was more likely to be screened for prostate cancer by PSA testing. Against the background of an enormous number of undiagnosed (but diagnosable) prostate cancers, this simple decision could lead to a prostate biopsy and exaggerate the link between family history and prostate cancer."
Findings
Their new findings are not entirely novel, admit Dr. Bratt and his coauthors.
Other researchers have found that there is an increased detection of prostate cancer shortly after a diagnosis of the disease in a family (J Natl Cancer Inst. 2005;97:1575-1579).
However, in their study, the Swedes added a few more details to what is understood about how PSA testing influences familial prostate cancer risk.
The study involved 22,511 brothers of 13,975 index patients with prostate cancer in the National Prostate Cancer Register of Sweden.
The investigators found, for the first time, that brothers of index patients who had a higher socioeconomic status (SIR, 4.2; 95% CI, 3.7 - 4.7) were more likely to be diagnosed with prostate cancer than brothers of index patients with a lower socioeconomic status (SIR, 2.8; 95% CI, 2.4 - 3.2).
The risk for T1c tumors (SIR, 3.4; 95% CI, 3.2 - 3.8), which are by definition diagnosed after a PSA test, was higher than for metastatic tumors (SIR, 2.0; 95% CI, 1.5 - 2.6), report the study authors.
And the risk for T1c tumors was highest during the first year after the diagnosis of the index patient (SIR, 4.3; 95% CI, 3.8 - 4.9), compared with the risk in the following years (SIR range, 2.8 to 3.3).
"The diagnostic activity among brothers of prostate cancer patients was especially high during the first year after a prostate cancer diagnosis in the family," the authors point out.
The study was funded by the Swedish Research Council, the Swedish Cancer Society, and Vasterbotten County Council. The authors have disclosed no relevant financial relationships.
J Natl Cancer Inst. Published online August 19, 2010. Abstract
ALCOHOL USE AND OBESITY LINKED TO INCREASED BREAST CANCER RECCURENCE
September 1, 2010 — Studies examining the relation between alcohol consumption and breast cancer have been decidedly mixed. But a paper published online August 30 in the Journal of Clinical Oncology reports that alcohol consumption appears to increase the risk for breast cancer recurrence.
"Clinicians should advise their breast cancer patients to possibly limit their consumption of alcohol," lead author Marilyn Kwan, PhD, a research scientist at Kaiser Permanente in Oakland, California, told Medscape Medical News. However, the data also suggest possible cardioprotective benefits associated with alcohol consumption, and Dr. Kwan acknowledged that the evidence can be difficult for patients to interpret.
"The most important advice I can give breast cancer patients is to talk with their clinician about any lifestyle changes they are considering after being diagnosed with breast cancer," Dr. Kwan said. "She can then fully evaluate the risks and benefits of consuming alcohol, and at what amount."
New Study Increases Evidence Base
"Our study increases the limited and mixed evidence base to date regarding the role of alcohol consumption and breast cancer prognosis; namely, that drinking moderate to heavy amounts of alcohol after a breast cancer diagnosis can possibly increase the risk of having a recurrence of breast cancer and dying from breast cancer," Dr. Kwan said.
"We found that alcohol negatively affects the prognosis of all women diagnosed with early-stage invasive breast cancer who consume at least 3 or 4 drinks per week, compared with women who did not consume any alcohol," she told Medscape Medical News.
The associations appeared stronger in overweight and/or postmenopausal women, which perhaps indicates that women in these subgroups are more susceptible to the effects of alcohol, she noted.
"Alcohol has been shown to increase estrogen metabolism and circulating estrogen levels in postmenopausal women, while being obese can also increase circulating sex hormones and insulin levels," Dr. Kwan explained. "In general, an overabundance of estrogen production can lead to breast cell proliferation and possible carcinogenic events in the breast tissue."
There was no association between alcohol intake and all-cause death. The authors note, however, that alcohol intake was possibly associated with a decreased risk for nonbreast cancer death, which would be consistent with current literature on "alcohol's likely protective effects on cardiovascular-related outcomes."
Elucidates a Mystery in the Literature
In an accompanying editorial, Michelle D. Holmes, MD, DrPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, notes that early detection and modern treatments have dramatically improved the prognosis for women with early-stage breast cancer.
"Clearly, women with breast cancer are living long enough to be vulnerable to death as a result of cardiovascular disease, which is still the number one cause of death among US women," she writes.
The study is important, she notes, because it "elucidates a mystery in the literature" concerning lifestyle factors that appear to affect breast cancer survival. The data in this study showed the "expected decrease in survival when recurrence and breast cancer death were used as end points, and no decrease in overall survival with alcohol intake," Dr. Holmes writes.
The study is also important because of the guidance it can give to individuals living with breast cancer and their physicians, she adds. "Their decision is the same as that facing woman without breast cancer; the answer is not a clear-cut yes or no."
"Moderate consumption of alcohol is likely to increase a woman's risk of dying as a result of breast cancer while decreasing her risk of dying as a result of heart disease," Dr. Holmes notes. "Whether to consume alcohol is an individual decision and is dependent on each woman's evaluation of and comfort level with those risks."
Strongest Effect Seen in Subgroups
In the study, Dr. Kwan and colleagues evaluated the association between alcohol and recurrence and mortality among early-stage breast cancer survivors. The prospective study consisted of 1897 women diagnosed with invasive early-stage breast cancer from 1997 to 2000 who were participating in the Life After Cancer Epidemiology (LACE) study.
Wine was the most common beverage among those who consumed alcohol (88.5%), followed by liquor (42.1%) and beer (35.7%); the median amount of alcohol consumed was 5.96 g/day. Within this cohort, women who were postmenopausal, normal weight, and estrogen-receptor (ER) positive tended to consume more alcohol than those who were premenopausal, overweight/obese, and ER-negative.
As of September 8, 2009, there were 293 breast cancer recurrences (of which 71.9% were distant metastases) and 273 deaths. Of the deaths that occurred, 154 (56.4%) were attributable to breast cancer, 24 (8.8%) to other cancers, 32 (11.7%) to cardiovascular causes, and 63 (23.1%) to other causes. Overall, the average follow-up time was 7.42 years (range, 0.11 to 9.62 years).
After adjustment for confounders such as age at diagnosis, prediagnosis body mass index (BMI), total folate intake, stage of disease, hormone-receptor status, tamoxifen use, treatment, and positive lymph nodes, the researchers found that consuming 6 g or more of alcohol per day, compared with no drinking, was possibly associated with an increased risk for breast cancer recurrence (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00 - 1.83) and breast cancer mortality (HR, 1.51; 95% CI, 1.00 - 2.29).
Drinking at least 2 servings of wine per week, compared with no wine, was also associated with an increased risk for disease recurrence (HR, 1.33; 95% CI, 0.97 - 1.81) and breast cancer death (HR, 1.37; 95% CI, 0.88 - 2.14), but a clear association was not seen for liquor or beer.
The data also suggest that alcohol consumption is associated with a decreased risk for death from causes unrelated to breast cancer (for less than 6 g/day, HR, 0.73; 95% CI, 0.45 - 1.20; for 6 g/day or more, HR, 0.77; 95% CI, 0.47 to 1.27).
The authors observed no association between overall death and drinking 6 g or more of alcohol per day.
When stratified by menopausal status, prediagnosis BMI, ER status, and risk for recurrence/breast cancer death, they found an association between consuming 6 g or more of alcohol per day with an increased risk for recurrence (HR, 1.51; 95% CI, 1.05 - 2.19) and breast cancer death (HR, 1.72; 95% CI, 1.05 - 2.81) among postmenopausal women. There was also a positive dose-response for greater alcohol intake and increasing risk (P for trend = .03 and .04, respectively).
No association was observed for premenopausal women.
Similarly, an association was seen among overweight and obese women, who had an increased risk for recurrence (HR, 1.60; 95% CI, 1.08 - 2.38) and an elevated but nonsignificant risk for breast cancer death (HR, 1.61; 95% CI, 0.94 - 2.76), with a positive dose-response (P for trend = .03 and .09, respectively).
Among women of normal weight, no associations were observed. The authors note that no difference in risk for recurrence or breast cancer death by ER status was observed for alcohol intake.
The study was supported by a grant from the National Cancer Institute. The authors and editorialist have disclosed no relevant financial relationships.
J Clin Oncol. Published online August 30, 2010.
"Clinicians should advise their breast cancer patients to possibly limit their consumption of alcohol," lead author Marilyn Kwan, PhD, a research scientist at Kaiser Permanente in Oakland, California, told Medscape Medical News. However, the data also suggest possible cardioprotective benefits associated with alcohol consumption, and Dr. Kwan acknowledged that the evidence can be difficult for patients to interpret.
"The most important advice I can give breast cancer patients is to talk with their clinician about any lifestyle changes they are considering after being diagnosed with breast cancer," Dr. Kwan said. "She can then fully evaluate the risks and benefits of consuming alcohol, and at what amount."
New Study Increases Evidence Base
"Our study increases the limited and mixed evidence base to date regarding the role of alcohol consumption and breast cancer prognosis; namely, that drinking moderate to heavy amounts of alcohol after a breast cancer diagnosis can possibly increase the risk of having a recurrence of breast cancer and dying from breast cancer," Dr. Kwan said.
"We found that alcohol negatively affects the prognosis of all women diagnosed with early-stage invasive breast cancer who consume at least 3 or 4 drinks per week, compared with women who did not consume any alcohol," she told Medscape Medical News.
The associations appeared stronger in overweight and/or postmenopausal women, which perhaps indicates that women in these subgroups are more susceptible to the effects of alcohol, she noted.
"Alcohol has been shown to increase estrogen metabolism and circulating estrogen levels in postmenopausal women, while being obese can also increase circulating sex hormones and insulin levels," Dr. Kwan explained. "In general, an overabundance of estrogen production can lead to breast cell proliferation and possible carcinogenic events in the breast tissue."
There was no association between alcohol intake and all-cause death. The authors note, however, that alcohol intake was possibly associated with a decreased risk for nonbreast cancer death, which would be consistent with current literature on "alcohol's likely protective effects on cardiovascular-related outcomes."
Elucidates a Mystery in the Literature
In an accompanying editorial, Michelle D. Holmes, MD, DrPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, notes that early detection and modern treatments have dramatically improved the prognosis for women with early-stage breast cancer.
"Clearly, women with breast cancer are living long enough to be vulnerable to death as a result of cardiovascular disease, which is still the number one cause of death among US women," she writes.
The study is important, she notes, because it "elucidates a mystery in the literature" concerning lifestyle factors that appear to affect breast cancer survival. The data in this study showed the "expected decrease in survival when recurrence and breast cancer death were used as end points, and no decrease in overall survival with alcohol intake," Dr. Holmes writes.
The study is also important because of the guidance it can give to individuals living with breast cancer and their physicians, she adds. "Their decision is the same as that facing woman without breast cancer; the answer is not a clear-cut yes or no."
"Moderate consumption of alcohol is likely to increase a woman's risk of dying as a result of breast cancer while decreasing her risk of dying as a result of heart disease," Dr. Holmes notes. "Whether to consume alcohol is an individual decision and is dependent on each woman's evaluation of and comfort level with those risks."
Strongest Effect Seen in Subgroups
In the study, Dr. Kwan and colleagues evaluated the association between alcohol and recurrence and mortality among early-stage breast cancer survivors. The prospective study consisted of 1897 women diagnosed with invasive early-stage breast cancer from 1997 to 2000 who were participating in the Life After Cancer Epidemiology (LACE) study.
Wine was the most common beverage among those who consumed alcohol (88.5%), followed by liquor (42.1%) and beer (35.7%); the median amount of alcohol consumed was 5.96 g/day. Within this cohort, women who were postmenopausal, normal weight, and estrogen-receptor (ER) positive tended to consume more alcohol than those who were premenopausal, overweight/obese, and ER-negative.
As of September 8, 2009, there were 293 breast cancer recurrences (of which 71.9% were distant metastases) and 273 deaths. Of the deaths that occurred, 154 (56.4%) were attributable to breast cancer, 24 (8.8%) to other cancers, 32 (11.7%) to cardiovascular causes, and 63 (23.1%) to other causes. Overall, the average follow-up time was 7.42 years (range, 0.11 to 9.62 years).
After adjustment for confounders such as age at diagnosis, prediagnosis body mass index (BMI), total folate intake, stage of disease, hormone-receptor status, tamoxifen use, treatment, and positive lymph nodes, the researchers found that consuming 6 g or more of alcohol per day, compared with no drinking, was possibly associated with an increased risk for breast cancer recurrence (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00 - 1.83) and breast cancer mortality (HR, 1.51; 95% CI, 1.00 - 2.29).
Drinking at least 2 servings of wine per week, compared with no wine, was also associated with an increased risk for disease recurrence (HR, 1.33; 95% CI, 0.97 - 1.81) and breast cancer death (HR, 1.37; 95% CI, 0.88 - 2.14), but a clear association was not seen for liquor or beer.
The data also suggest that alcohol consumption is associated with a decreased risk for death from causes unrelated to breast cancer (for less than 6 g/day, HR, 0.73; 95% CI, 0.45 - 1.20; for 6 g/day or more, HR, 0.77; 95% CI, 0.47 to 1.27).
The authors observed no association between overall death and drinking 6 g or more of alcohol per day.
When stratified by menopausal status, prediagnosis BMI, ER status, and risk for recurrence/breast cancer death, they found an association between consuming 6 g or more of alcohol per day with an increased risk for recurrence (HR, 1.51; 95% CI, 1.05 - 2.19) and breast cancer death (HR, 1.72; 95% CI, 1.05 - 2.81) among postmenopausal women. There was also a positive dose-response for greater alcohol intake and increasing risk (P for trend = .03 and .04, respectively).
No association was observed for premenopausal women.
Similarly, an association was seen among overweight and obese women, who had an increased risk for recurrence (HR, 1.60; 95% CI, 1.08 - 2.38) and an elevated but nonsignificant risk for breast cancer death (HR, 1.61; 95% CI, 0.94 - 2.76), with a positive dose-response (P for trend = .03 and .09, respectively).
Among women of normal weight, no associations were observed. The authors note that no difference in risk for recurrence or breast cancer death by ER status was observed for alcohol intake.
The study was supported by a grant from the National Cancer Institute. The authors and editorialist have disclosed no relevant financial relationships.
J Clin Oncol. Published online August 30, 2010.
RAPID MOLECULAR TEST FOR SPUTUM DETECTION FO TB
September 2, 2010 — A rapid molecular test for sputum (Xpert MTB/RIF; Cepheid) detects tuberculosis and rifampin resistance, according to the results of a study reported online September 1 in the New England Journal of Medicine.
"Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection," write Catharina C. Boehme, MD, from the Foundation for Innovative New Diagnostics in Geneva, Switzerland, and colleagues. "Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect."
In this study, 1730 patients from Peru, Azerbaijan, South Africa, and India with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis were tested with MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and rifampin resistance (RIF). Each patient provided 3 specimens, 2 of which were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and 1 of which was tested directly with microscopy and the MTB/RIF test.
For patients with positive tuberculosis culture, a single MTB/RIF test was positive in 551 of 561 patients (98.2%) with positive smear for tuberculosis and was negative in 124 of 171 patients (72.5%) with negative smear. Specificity of the MTB/RIF test in patients without tuberculosis was 99.2% (604/609 patients).
For patients with positive tuberculosis culture but negative smear, adding a second MTB/RIF test increased sensitivity by 12.6 percentage points, and adding a third increased sensitivity by 5.1 percentage points — improving sensitivity to 90.2%.
MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 518 patients (98.1%) with rifampin-sensitive bacteria, based on phenotypic drug-susceptibility testing. Sequencing resolved all but 2 cases in favor of the MTB/RIF test.
"The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time," the study authors write.
Limitations of this study include a possible lack of generalizability to settings with less controlled conditions, and the high costs of the manufacturing technology needed for the MTB/RIF test.
In an accompanying editorial, Peter M. Small, MD, from the Global Health Program, Bill and Melinda Gates Foundation, and the Institute for Systems Biology in Seattle, Washington, and Madhukar Pai, MD, from McGill University and the Montreal Chest Institute in Montreal, Canada, note the challenges involved in ensuring availability of the MTB/RIF test and similar technology.
"Emerging economies have the potential to become global leaders in innovative product development and delivery," Dr. Small and Dr. Pai write. "If these countries successfully tackle their own tuberculosis problems, the elimination of tuberculosis by 2050 might become a reality."
The Foundation for Innovative New Diagnostics, the National Institutes of Health, and the Bill and Melinda Gates Foundation supported this study. Several study authors have disclosed receiving reimbursement from the Foundation for Innovative New Diagnostics and/or from the National Institute of Allergy and Infectious Diseases in the form of individual and/or institutional grants, travel support, honoraria, and/or consultancy fees. Several authors also disclose serving as board members or employees for and/or receiving stock options, travel support, and/or grant funding from Cepheid. Dr. Small was a founding board member of the Foundation for Innovative New Diagnostics, is an employee of the Bill and Melinda Gates Foundation, and owns stock or stock options in Johnson & Johnson.
N Engl J Med. Published online September 1, 2010.
"Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection," write Catharina C. Boehme, MD, from the Foundation for Innovative New Diagnostics in Geneva, Switzerland, and colleagues. "Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect."
In this study, 1730 patients from Peru, Azerbaijan, South Africa, and India with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis were tested with MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and rifampin resistance (RIF). Each patient provided 3 specimens, 2 of which were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and 1 of which was tested directly with microscopy and the MTB/RIF test.
For patients with positive tuberculosis culture, a single MTB/RIF test was positive in 551 of 561 patients (98.2%) with positive smear for tuberculosis and was negative in 124 of 171 patients (72.5%) with negative smear. Specificity of the MTB/RIF test in patients without tuberculosis was 99.2% (604/609 patients).
For patients with positive tuberculosis culture but negative smear, adding a second MTB/RIF test increased sensitivity by 12.6 percentage points, and adding a third increased sensitivity by 5.1 percentage points — improving sensitivity to 90.2%.
MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 518 patients (98.1%) with rifampin-sensitive bacteria, based on phenotypic drug-susceptibility testing. Sequencing resolved all but 2 cases in favor of the MTB/RIF test.
"The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time," the study authors write.
Limitations of this study include a possible lack of generalizability to settings with less controlled conditions, and the high costs of the manufacturing technology needed for the MTB/RIF test.
In an accompanying editorial, Peter M. Small, MD, from the Global Health Program, Bill and Melinda Gates Foundation, and the Institute for Systems Biology in Seattle, Washington, and Madhukar Pai, MD, from McGill University and the Montreal Chest Institute in Montreal, Canada, note the challenges involved in ensuring availability of the MTB/RIF test and similar technology.
"Emerging economies have the potential to become global leaders in innovative product development and delivery," Dr. Small and Dr. Pai write. "If these countries successfully tackle their own tuberculosis problems, the elimination of tuberculosis by 2050 might become a reality."
The Foundation for Innovative New Diagnostics, the National Institutes of Health, and the Bill and Melinda Gates Foundation supported this study. Several study authors have disclosed receiving reimbursement from the Foundation for Innovative New Diagnostics and/or from the National Institute of Allergy and Infectious Diseases in the form of individual and/or institutional grants, travel support, honoraria, and/or consultancy fees. Several authors also disclose serving as board members or employees for and/or receiving stock options, travel support, and/or grant funding from Cepheid. Dr. Small was a founding board member of the Foundation for Innovative New Diagnostics, is an employee of the Bill and Melinda Gates Foundation, and owns stock or stock options in Johnson & Johnson.
N Engl J Med. Published online September 1, 2010.
FOLFOX FOR APPENDICAL ADENOCARCINOMA
J Surg Oncol. 2010 Aug 24. [Epub ahead of print]
Neoadjuvant FOLFOX chemotherapy in 34 consecutive patients with mucinous peritoneal carcinomatosis of appendiceal origin.
Sugarbaker PH, Bijelic L, Chang D, Yoo D.
Washington Cancer Institute, Washington, District of Columbia.
Abstract
BACKGROUND: A treatment option for patients with peritoneal mucinous carcinomatosis (PMCA) from an appendiceal neoplasm is cytoreductive surgery and perioperative intraperitoneal chemotherapy. Also, these patients are recommended for systemic chemotherapy using an oxaliplatin and 5-fluorouracil (FOLFOX) regimen. A major question concerns the proper timing (neoadjuvant vs. adjuvant) of the systemic chemotherapy.
METHODS: In January of 2005 a prospective study was initiated to routinely treat patients with peritoneal dissemination of a mucinous adenocarcinoma of the appendix with neoadjuvant chemotherapy using FOLFOX. All patients had a clinical, CT, intraoperative, and histopathological assessment of chemotherapy effects. The study was closed in July of 2009.
RESULTS: Thirty-four consecutive patients were available for evaluation. In the clinical evaluation and CT evaluation, 24 (71%) and 22 (65%), respectively, had stable disease on chemotherapy. By intraoperative examination 17 (50%) patients were observed to have progressed. By histopathology seven had a partial response and three patients a complete response (29%).
CONCLUSIONS: In these carcinomatosis patients clinical and CT assessment of response to neoadjuvant chemotherapy seldom provided useful data over this short time period. Intraoperative findings indicated progression in 50% of patients. By histopathology, 29% of patients had a response. J. Surg. Oncol. (c) 2010 Wiley-Liss, Inc.
Neoadjuvant FOLFOX chemotherapy in 34 consecutive patients with mucinous peritoneal carcinomatosis of appendiceal origin.
Sugarbaker PH, Bijelic L, Chang D, Yoo D.
Washington Cancer Institute, Washington, District of Columbia.
Abstract
BACKGROUND: A treatment option for patients with peritoneal mucinous carcinomatosis (PMCA) from an appendiceal neoplasm is cytoreductive surgery and perioperative intraperitoneal chemotherapy. Also, these patients are recommended for systemic chemotherapy using an oxaliplatin and 5-fluorouracil (FOLFOX) regimen. A major question concerns the proper timing (neoadjuvant vs. adjuvant) of the systemic chemotherapy.
METHODS: In January of 2005 a prospective study was initiated to routinely treat patients with peritoneal dissemination of a mucinous adenocarcinoma of the appendix with neoadjuvant chemotherapy using FOLFOX. All patients had a clinical, CT, intraoperative, and histopathological assessment of chemotherapy effects. The study was closed in July of 2009.
RESULTS: Thirty-four consecutive patients were available for evaluation. In the clinical evaluation and CT evaluation, 24 (71%) and 22 (65%), respectively, had stable disease on chemotherapy. By intraoperative examination 17 (50%) patients were observed to have progressed. By histopathology seven had a partial response and three patients a complete response (29%).
CONCLUSIONS: In these carcinomatosis patients clinical and CT assessment of response to neoadjuvant chemotherapy seldom provided useful data over this short time period. Intraoperative findings indicated progression in 50% of patients. By histopathology, 29% of patients had a response. J. Surg. Oncol. (c) 2010 Wiley-Liss, Inc.
LIMIT FINGERSTICK DEVICES TO ONE PERSON
August 27, 2010 — In the war against the transmission of bloodborne pathogens such as hepatitis B virus, the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) recommended yesterday that fingerstick devices should never be used with more than 1 person. They issued similar guidance for point-of-care (POC) blood-testing devices such as glucometers and instruments for insulin administration.
The 2 federal agencies said the shared used of blood lancing and POC testing devices has led to a steady rise in reports of bloodborne-pathogen infections — mostly involving hepatitis B virus — during the past 10 to 15 years. Such communal bloodletting occurs in settings that range from public health fairs to physician offices, but the problem is most serious in long-term care and assisted-living facilities.
In addition to stipulating a rule of 1 fingerstick device for 1 person, the FDA and CDC recommended that when clinicians obtain blood samples to monitor blood glucose levels, they should rely on fingerstick devices that automatically disable themselves after a single use — those in which the blade retracts, for example. These single-use, auto-disabling instruments are also known as safety lancets.
The new recommendation applies to fingerstick devices that are approved for obtaining blood from multiple individuals. The FDA stated that it would soon take action to have these items labeled for use with only a single person.
Insulin Pens Also Should Not Be Shared
The FDA and CDC did not take as tough of a precautionary stand on POC testing devices such as blood glucose and anticoagulation meters. They recommended that these devices should be used with only 1 person "whenever possible." However, if it is not possible to dedicate a POC testing device to a single patient, clinicians should properly clean and disinfect the device between every use, as described in the product label.
The same concerns about preventing the spread of bloodborne pathogens extend to insulin administration. Insulin pens — which contain several doses of insulin that patients can administer to themselves — should never be shared, according to the FDA and CDC. When clinicians assign them to patients, the devices should be labeled for single-patient use.
Whenever possible, multidose vials of insulin should be limited to a single person. If not, the vials should be stored and prepared in a dedicated area away from the patient care environment and potentially contaminated equipment. Insulin should always be administered with a new needle and syringe, which likewise should never be used to administer insulin to more than 1 person, and then "disposed of immediately after use in an approved sharps container."
Physicians should wear gloves for any task that potentially exposes them to blood or body fluids, and they should change gloves between patient contacts, even when they work with patient-dedicated POC devices or single-use, self-disabling fingerstick devices.
More information about the warning is available on the Web sites of the FDA and the CDC.
The 2 federal agencies said the shared used of blood lancing and POC testing devices has led to a steady rise in reports of bloodborne-pathogen infections — mostly involving hepatitis B virus — during the past 10 to 15 years. Such communal bloodletting occurs in settings that range from public health fairs to physician offices, but the problem is most serious in long-term care and assisted-living facilities.
In addition to stipulating a rule of 1 fingerstick device for 1 person, the FDA and CDC recommended that when clinicians obtain blood samples to monitor blood glucose levels, they should rely on fingerstick devices that automatically disable themselves after a single use — those in which the blade retracts, for example. These single-use, auto-disabling instruments are also known as safety lancets.
The new recommendation applies to fingerstick devices that are approved for obtaining blood from multiple individuals. The FDA stated that it would soon take action to have these items labeled for use with only a single person.
Insulin Pens Also Should Not Be Shared
The FDA and CDC did not take as tough of a precautionary stand on POC testing devices such as blood glucose and anticoagulation meters. They recommended that these devices should be used with only 1 person "whenever possible." However, if it is not possible to dedicate a POC testing device to a single patient, clinicians should properly clean and disinfect the device between every use, as described in the product label.
The same concerns about preventing the spread of bloodborne pathogens extend to insulin administration. Insulin pens — which contain several doses of insulin that patients can administer to themselves — should never be shared, according to the FDA and CDC. When clinicians assign them to patients, the devices should be labeled for single-patient use.
Whenever possible, multidose vials of insulin should be limited to a single person. If not, the vials should be stored and prepared in a dedicated area away from the patient care environment and potentially contaminated equipment. Insulin should always be administered with a new needle and syringe, which likewise should never be used to administer insulin to more than 1 person, and then "disposed of immediately after use in an approved sharps container."
Physicians should wear gloves for any task that potentially exposes them to blood or body fluids, and they should change gloves between patient contacts, even when they work with patient-dedicated POC devices or single-use, self-disabling fingerstick devices.
More information about the warning is available on the Web sites of the FDA and the CDC.
METFORMIN REDUCES CANCER RISK
September 3, 2010 — The chance observation that diabetes patients taking metformin have a 40% reduced risk for cancer triggered intense research interest in this old off-patent drug.
Data from a small clinical trial and from an animal study reported in the September issue of Cancer Prevention Research suggest that metformin might suppress the development of precancerous colorectal lesions in humans and prevent tobacco-induced lung cancers in mice. The drug appears to alter cellular energy metabolism in a way that is particularly bad for cancers and precancerous cells. It is also attractive because it is relatively nontoxic.
During a press briefing organized by the American Association for Cancer Research to discuss the metformin data, Michael Pollak, MD, from McGill University in Montreal, Quebec, said that the new studies are important because they indicate the usefulness of metformin as a preventive agent. Dr. Pollak wrote a review of metformin and other biguanides in oncology that appears in the same issue of Cancer Prevention Research.
"Unlike chemotherapy or radiotherapy, which are intended to kill cancer cells in a directly toxic manner, metformin appears to target the cancer in a more subtle way, which involves cancer energetics. It also may act in some patients, especially diabetic cancer patients, by reducing levels of hormones that can stimulate cell growth, including insulin itself," Dr. Pollak said.
In the first human trial of metformin as a cancer preventive, Kunihiro Hosono, MD, and colleagues from the Yokohama City University School of Medicine in Japan report that nondiabetic patients randomized to 1 month of low-dose of metformin (250 mg/day) had a significant decrease in the mean number of rectal aberrant crypt foci (ACF), an endoscopic surrogate marker of colorectal cancer.
The researchers randomized 12 nondiabetic patients with ACF to treatment with metformin and 14 to no treatment. After 1 month, the metformin patients not only had fewer ACFs, they also had significant decreases in the proliferating cell nuclear antigen index.
Dr. Hosono and colleagues write that "this first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer."
Low-dose metformin did not cause any adverse effects, such as lactic acidosis, hypoglycemia, or diarrhea in this study.
In related work, a research team led by Phillip A. Dennis, MD, and Regan M. Memmott, MD, from the National Cancer Institute (NCI) Medical Oncology Branch in Bethesda, Maryland, studied metformin for prevention in a mouse model of smoking-related lung cancer. They exposed mice to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and then treated the mice with metformin in drinking water.
The researchers expected that a specific target (the rapamycin or mTOR pathway, an early event in tobacco-induced lung cancer) would be inhibited by metformin.
"After about 10% of the mouse lifespan — about 12 weeks — with the highest dose in the drinking water, we found a 33% reduction in tumor multiplicity and a 34% reduction in tumor size in the mice. In mice that did not get metformin, 100% got tobacco carcinogen-induced lung tumors," Dr. Dennis said at the press briefing. Overall, metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that can be achieved in humans.
Despite this, mTOR was only modestly inhibited, so the researchers moved to intraperitoeal administration to achieve higher dose levels. This showed that metformin activated 5′-AMP-activated protein kinase in liver tissue (but not lung tissue), where it inhibited phosphorylation of the insulin-like growth factor (IGF)-1/insulin receptor. Mice injected with metformin daily for 12 weeks had a 72% reduction in tumor burden.
"We think that metformin was able to inhibit lung tumorigenesis caused by a tobacco carcinogen — when given in drinking water to achieve levels that could be attained in humans and when given by injection — and that the mechanism involves hormone release from the liver. We are planning to move forward to study metformin as a chemopreventive agent in clinical trials," Dr. Dennis said.
Lewis Cantley, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, suggested at the press briefing that metformin might prevent tumors by reducing levels of insulin and IGF-1. He noted that 2 approaches to treating type 2 diabetes (insulin, which increases insulin levels, and metformin, which decreases them) appear to have opposite effects on cancer risk.
Dr. Pollak said that "metformin's effects in animals are similar to those of a brief period of fasting. On a normal diet, metformin fools the liver into thinking it is fasting."
It fell to Dr. Cantley to mention the elephant in the room: metformin is off patent and unlikely to attract pharmaceutical industry support for clinical trials to established the drug as a general cancer preventive. "This will have to have millions of dollars in either private or NCI support," he said.
Dr. Pollak reports consulting for Merck, Novo-Nordisk, Lilly, Pfizer, and Sanofi-Aventis. Dr. Hosono and Dr. Dennis have disclosed no relevant financial relationships. Dr. Cantley is founder of and a consultant for Agios.
Cancer Prev Res (Phila Pa). 2010;3:1049-1052, 1060-1065, 1066-1076, 1077-1083.
Data from a small clinical trial and from an animal study reported in the September issue of Cancer Prevention Research suggest that metformin might suppress the development of precancerous colorectal lesions in humans and prevent tobacco-induced lung cancers in mice. The drug appears to alter cellular energy metabolism in a way that is particularly bad for cancers and precancerous cells. It is also attractive because it is relatively nontoxic.
During a press briefing organized by the American Association for Cancer Research to discuss the metformin data, Michael Pollak, MD, from McGill University in Montreal, Quebec, said that the new studies are important because they indicate the usefulness of metformin as a preventive agent. Dr. Pollak wrote a review of metformin and other biguanides in oncology that appears in the same issue of Cancer Prevention Research.
"Unlike chemotherapy or radiotherapy, which are intended to kill cancer cells in a directly toxic manner, metformin appears to target the cancer in a more subtle way, which involves cancer energetics. It also may act in some patients, especially diabetic cancer patients, by reducing levels of hormones that can stimulate cell growth, including insulin itself," Dr. Pollak said.
In the first human trial of metformin as a cancer preventive, Kunihiro Hosono, MD, and colleagues from the Yokohama City University School of Medicine in Japan report that nondiabetic patients randomized to 1 month of low-dose of metformin (250 mg/day) had a significant decrease in the mean number of rectal aberrant crypt foci (ACF), an endoscopic surrogate marker of colorectal cancer.
The researchers randomized 12 nondiabetic patients with ACF to treatment with metformin and 14 to no treatment. After 1 month, the metformin patients not only had fewer ACFs, they also had significant decreases in the proliferating cell nuclear antigen index.
Dr. Hosono and colleagues write that "this first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer."
Low-dose metformin did not cause any adverse effects, such as lactic acidosis, hypoglycemia, or diarrhea in this study.
In related work, a research team led by Phillip A. Dennis, MD, and Regan M. Memmott, MD, from the National Cancer Institute (NCI) Medical Oncology Branch in Bethesda, Maryland, studied metformin for prevention in a mouse model of smoking-related lung cancer. They exposed mice to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and then treated the mice with metformin in drinking water.
The researchers expected that a specific target (the rapamycin or mTOR pathway, an early event in tobacco-induced lung cancer) would be inhibited by metformin.
"After about 10% of the mouse lifespan — about 12 weeks — with the highest dose in the drinking water, we found a 33% reduction in tumor multiplicity and a 34% reduction in tumor size in the mice. In mice that did not get metformin, 100% got tobacco carcinogen-induced lung tumors," Dr. Dennis said at the press briefing. Overall, metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that can be achieved in humans.
Despite this, mTOR was only modestly inhibited, so the researchers moved to intraperitoeal administration to achieve higher dose levels. This showed that metformin activated 5′-AMP-activated protein kinase in liver tissue (but not lung tissue), where it inhibited phosphorylation of the insulin-like growth factor (IGF)-1/insulin receptor. Mice injected with metformin daily for 12 weeks had a 72% reduction in tumor burden.
"We think that metformin was able to inhibit lung tumorigenesis caused by a tobacco carcinogen — when given in drinking water to achieve levels that could be attained in humans and when given by injection — and that the mechanism involves hormone release from the liver. We are planning to move forward to study metformin as a chemopreventive agent in clinical trials," Dr. Dennis said.
Lewis Cantley, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, suggested at the press briefing that metformin might prevent tumors by reducing levels of insulin and IGF-1. He noted that 2 approaches to treating type 2 diabetes (insulin, which increases insulin levels, and metformin, which decreases them) appear to have opposite effects on cancer risk.
Dr. Pollak said that "metformin's effects in animals are similar to those of a brief period of fasting. On a normal diet, metformin fools the liver into thinking it is fasting."
It fell to Dr. Cantley to mention the elephant in the room: metformin is off patent and unlikely to attract pharmaceutical industry support for clinical trials to established the drug as a general cancer preventive. "This will have to have millions of dollars in either private or NCI support," he said.
Dr. Pollak reports consulting for Merck, Novo-Nordisk, Lilly, Pfizer, and Sanofi-Aventis. Dr. Hosono and Dr. Dennis have disclosed no relevant financial relationships. Dr. Cantley is founder of and a consultant for Agios.
Cancer Prev Res (Phila Pa). 2010;3:1049-1052, 1060-1065, 1066-1076, 1077-1083.
Πέμπτη 2 Σεπτεμβρίου 2010
PROPHYLACTIC SURGERY FOR BRCA MUTATION CARRIERS
August 31, 2010 — A large new study has confirmed the benefits of prophylactic mastectomy and salpingo-oophorectomy in women with BRCA1 and BRCA2 mutations. Women who underwent the prophylactic surgery had a greatly reduced risk for breast or ovarian cancer and a reduction in cancer-related mortality.
The findings appear in the September 1 issue of the Journal of the American Medical Association.
This study adds evidence supporting the benefits of preventive surgery — that it can reduce the risk for cancer-related mortality and for breast/ovarian cancer developing in the first place, explained senior author Timothy Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania School of Medicine in Philadelphia.
Dr. Rebbeck and colleagues investigated a cohort of nearly 2500 women with BRCA1 or BRCA2 mutations, 10% of whom chose to undergo a risk-reducing mastectomy and 38% of whom chose a risk-reducing salpingo-oophorectomy.
No breast cancers were diagnosed in the women who underwent mastectomy during the 3 years of prospective follow-up. However, 7% of those who did not undergo a prophylactic mastectomy during a similar follow-up period were diagnosed with breast cancer.
There were no cases of ovarian cancer events during the 6 years of prospective follow-up in BRCA2 carriers without previous breast cancer who underwent salpingo-oophorectomy. Conversely, 3% of women who did not undergo the procedure over a similar follow-up period were diagnosed with the disease.
Among BRCA1 carriers with a previous diagnosis of breast cancer, undergoing a salpingo-oophorectomy was associated with a reduced risk for ovarian cancer (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 - 0.63); there were no cases diagnosed in BRCA2 carriers.
Overall, results showed that, compared with women who did not undergo prophylactic salpingo-oophorectomy, those who underwent the procedure had an overall lower risk for ovarian cancer, including those with previous breast cancer (6% vs 1%; HR, 0.14; 95% CI, 0.04 - 0.59) and those without previous breast cancer (6% vs 2%; HR, 0.28; 95% CI, 0.12 - 0.6); a lower risk for first diagnosis of breast cancer in BRCA1 carriers (20% vs 14%; HR, 0.63; 95% CI, 0.41 - 0.96) and BRCA2 carriers (23% vs 7%; HR, 0.36; 95% CI, 0.16 - 0.82); lower all-cause mortality (10% vs 3%; HR, 0.40; 95% CI, 0.26 - 0.61); lower breast-cancer-specific mortality (6% vs 2%; HR, 0.44; 95% CI, 0.26 - 0.76); and lower ovarian-cancer-specific mortality (3% vs 0.4%; HR, 0.21; 95% CI, 0.06 - 0.80).
Data for Surveillance Group Limited
The women who opted not to have prophylactic surgery were counseled to undergo intensive screening. Although surveillance isn't prevention, it can result in earlier detection and improved survival, but the nonsurgery group of the study was not specifically evaluated for surveillance practices, said Dr. Rebbeck.
"We don't have data on the survival or mortality in women who underwent optimal screening," he told Medscape Medical News. "Having said that, the breast cancer risk reduction among women in the oophorectomy group is substantial but comparable to that in the general population of women who took tamoxifen."
There are no data to date for women with BRCA1/2 mutations and primary prevention of breast cancer with tamoxifen use, he added. "While there are no comparison data available, it may be possible that the risk reduction by oophorectomy is comparable to that of other measures."
But Dr. Rebbeck emphasized that an important point to remember is that oophorectomy is primarily recommended to reduce ovarian cancer risk or death, not breast cancer. "Women should be using oophorectomy as an ovarian cancer prevention tool — the benefit to breast cancer is just a side benefit," he said.
Importance of Counseling, Fear of Genetic Testing
It is important to identify and counsel women who have a family history of breast cancer, so that they will better understand their risks and options, and ways to reduce those risks, note the authors of an accompanying editorial.
"At a minimum, primary care clinicians should be familiar with the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines and should be able to refer at-risk patients to a genetic counselor," write Laura Esserman, MD, MBA, from University of California, San Francisco, and Virginia Kaklamani, MD, DSc, from Northwestern University, Chicago, Illinois.
The editorialists point out that now that there are better data available on the potential outcomes of these interventions, women can make more informed choices about whether to opt for prophylactic surgery or intensive surveillance.
But even though the techniques for prophylactic surgery and cosmetic options have improved, many women still might not opt for this. In such cases, there are other approaches that are less invasive than surgery but more aggressive than surveillance, explained Dr. Kaklamani.
"We have chemopreventive agents such as tamoxifen that can help, and there are other agents that are being tested, such as PARP inhibitors," she told Medscape Medical News.
In addition, some people fear the implications that positive genetic tests, including those for BRCA mutations, can have on their insurance premiums. The Genetic Information Nondiscrimination Act of 2008 was designed to protect people from insurance and employer discrimination on the basis of genetic tests, and Dr. Kaklamani emphasized the importance of educating women about this.
"There are laws that protect us from insurance discrimination from genetic testing and, with this study, we now know that procedures that we recommend have a positive impact on survival," she said.
Evidence Added
The study adds to the growing body of literature concerning the benefits of prophylactic surgery for women with BRCA1/2 mutations. As previously reported by Medscape Medical News, 4 separate analyses showed that having a bilateral mastectomy reduced the risk for breast cancer by 90%.
Another study found that women carrying the BRCA gene mutation who underwent a prophylactic mastectomy reduced their risk for breast cancer to less than 1%. Although estimates vary, mutation carriers have an approximate lifetime risk for breast cancer that ranges from 56% to 84%.
Improved Research Mechanisms Needed
"The discovery of biomarkers that identify high-risk individuals for a specific disease and integration of these biomarkers into clinical practice enables the systematic study of these populations — and development and testing of interventions to reduce their risk," write the editorialists.
They note that the study required more than 20 collaborating clinical centers to collect data from thousands of women who participated in the research, and point out that better methods are needed.
Improved mechanisms are needed to study and evaluate "the introduction of new tests, like BRCA gene mutation testing, and to capture key pieces of de-identified information — such as the uptake of testing, results, clinical decisions, and outcomes — so that clinicians and researchers can continually learn from their experience," they write.
The study was supported by grants and funding from the Public Health Service, the University of Pennsylvania Cancer Center, the Cancer Genetics Network, the Marjorie Cohen Research Fund, SPORE grant from the Dana-Farber/Harvard Cancer Center, the US Department of Defense, the Utah Cancer Registry and the Utah State Department of Health, Nebraska State Cancer and Smoking-Related Diseases Research Program, Cancer Research UK, National Cancer Institute, and the National Institute for Health Research. Olufunmilayo I. Olopade, MD, a coauthor of the study, from the University of Chicago Medical Center in Illinois, has received funding as the Doris Duke Distinguished Clinical Scientist. The other study authors and the editorialists have disclosed no relevant financial relationships.
JAMA. 2010;304:967-975, 1011-1012.
The findings appear in the September 1 issue of the Journal of the American Medical Association.
This study adds evidence supporting the benefits of preventive surgery — that it can reduce the risk for cancer-related mortality and for breast/ovarian cancer developing in the first place, explained senior author Timothy Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania School of Medicine in Philadelphia.
Dr. Rebbeck and colleagues investigated a cohort of nearly 2500 women with BRCA1 or BRCA2 mutations, 10% of whom chose to undergo a risk-reducing mastectomy and 38% of whom chose a risk-reducing salpingo-oophorectomy.
No breast cancers were diagnosed in the women who underwent mastectomy during the 3 years of prospective follow-up. However, 7% of those who did not undergo a prophylactic mastectomy during a similar follow-up period were diagnosed with breast cancer.
There were no cases of ovarian cancer events during the 6 years of prospective follow-up in BRCA2 carriers without previous breast cancer who underwent salpingo-oophorectomy. Conversely, 3% of women who did not undergo the procedure over a similar follow-up period were diagnosed with the disease.
Among BRCA1 carriers with a previous diagnosis of breast cancer, undergoing a salpingo-oophorectomy was associated with a reduced risk for ovarian cancer (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 - 0.63); there were no cases diagnosed in BRCA2 carriers.
Overall, results showed that, compared with women who did not undergo prophylactic salpingo-oophorectomy, those who underwent the procedure had an overall lower risk for ovarian cancer, including those with previous breast cancer (6% vs 1%; HR, 0.14; 95% CI, 0.04 - 0.59) and those without previous breast cancer (6% vs 2%; HR, 0.28; 95% CI, 0.12 - 0.6); a lower risk for first diagnosis of breast cancer in BRCA1 carriers (20% vs 14%; HR, 0.63; 95% CI, 0.41 - 0.96) and BRCA2 carriers (23% vs 7%; HR, 0.36; 95% CI, 0.16 - 0.82); lower all-cause mortality (10% vs 3%; HR, 0.40; 95% CI, 0.26 - 0.61); lower breast-cancer-specific mortality (6% vs 2%; HR, 0.44; 95% CI, 0.26 - 0.76); and lower ovarian-cancer-specific mortality (3% vs 0.4%; HR, 0.21; 95% CI, 0.06 - 0.80).
Data for Surveillance Group Limited
The women who opted not to have prophylactic surgery were counseled to undergo intensive screening. Although surveillance isn't prevention, it can result in earlier detection and improved survival, but the nonsurgery group of the study was not specifically evaluated for surveillance practices, said Dr. Rebbeck.
"We don't have data on the survival or mortality in women who underwent optimal screening," he told Medscape Medical News. "Having said that, the breast cancer risk reduction among women in the oophorectomy group is substantial but comparable to that in the general population of women who took tamoxifen."
There are no data to date for women with BRCA1/2 mutations and primary prevention of breast cancer with tamoxifen use, he added. "While there are no comparison data available, it may be possible that the risk reduction by oophorectomy is comparable to that of other measures."
But Dr. Rebbeck emphasized that an important point to remember is that oophorectomy is primarily recommended to reduce ovarian cancer risk or death, not breast cancer. "Women should be using oophorectomy as an ovarian cancer prevention tool — the benefit to breast cancer is just a side benefit," he said.
Importance of Counseling, Fear of Genetic Testing
It is important to identify and counsel women who have a family history of breast cancer, so that they will better understand their risks and options, and ways to reduce those risks, note the authors of an accompanying editorial.
"At a minimum, primary care clinicians should be familiar with the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines and should be able to refer at-risk patients to a genetic counselor," write Laura Esserman, MD, MBA, from University of California, San Francisco, and Virginia Kaklamani, MD, DSc, from Northwestern University, Chicago, Illinois.
The editorialists point out that now that there are better data available on the potential outcomes of these interventions, women can make more informed choices about whether to opt for prophylactic surgery or intensive surveillance.
But even though the techniques for prophylactic surgery and cosmetic options have improved, many women still might not opt for this. In such cases, there are other approaches that are less invasive than surgery but more aggressive than surveillance, explained Dr. Kaklamani.
"We have chemopreventive agents such as tamoxifen that can help, and there are other agents that are being tested, such as PARP inhibitors," she told Medscape Medical News.
In addition, some people fear the implications that positive genetic tests, including those for BRCA mutations, can have on their insurance premiums. The Genetic Information Nondiscrimination Act of 2008 was designed to protect people from insurance and employer discrimination on the basis of genetic tests, and Dr. Kaklamani emphasized the importance of educating women about this.
"There are laws that protect us from insurance discrimination from genetic testing and, with this study, we now know that procedures that we recommend have a positive impact on survival," she said.
Evidence Added
The study adds to the growing body of literature concerning the benefits of prophylactic surgery for women with BRCA1/2 mutations. As previously reported by Medscape Medical News, 4 separate analyses showed that having a bilateral mastectomy reduced the risk for breast cancer by 90%.
Another study found that women carrying the BRCA gene mutation who underwent a prophylactic mastectomy reduced their risk for breast cancer to less than 1%. Although estimates vary, mutation carriers have an approximate lifetime risk for breast cancer that ranges from 56% to 84%.
Improved Research Mechanisms Needed
"The discovery of biomarkers that identify high-risk individuals for a specific disease and integration of these biomarkers into clinical practice enables the systematic study of these populations — and development and testing of interventions to reduce their risk," write the editorialists.
They note that the study required more than 20 collaborating clinical centers to collect data from thousands of women who participated in the research, and point out that better methods are needed.
Improved mechanisms are needed to study and evaluate "the introduction of new tests, like BRCA gene mutation testing, and to capture key pieces of de-identified information — such as the uptake of testing, results, clinical decisions, and outcomes — so that clinicians and researchers can continually learn from their experience," they write.
The study was supported by grants and funding from the Public Health Service, the University of Pennsylvania Cancer Center, the Cancer Genetics Network, the Marjorie Cohen Research Fund, SPORE grant from the Dana-Farber/Harvard Cancer Center, the US Department of Defense, the Utah Cancer Registry and the Utah State Department of Health, Nebraska State Cancer and Smoking-Related Diseases Research Program, Cancer Research UK, National Cancer Institute, and the National Institute for Health Research. Olufunmilayo I. Olopade, MD, a coauthor of the study, from the University of Chicago Medical Center in Illinois, has received funding as the Doris Duke Distinguished Clinical Scientist. The other study authors and the editorialists have disclosed no relevant financial relationships.
JAMA. 2010;304:967-975, 1011-1012.
LAPATINIB USE FOR BREAST CANCER
Expert Rev Anticancer Ther. 2010 Aug;10(8):1171-82.
Lapatinib and breast cancer: current indications and outlook for the future.
Moreira C, Kaklamani V.
Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine of Northwestern University and the Robert H Lurie Comprehensive Cancer Center, 676 North St Clair Street, Suite 850, Chicago, IL 60611, USA.
Abstract
Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 (HER2) and blocks the EGF receptor. Studies have shown that in patients with metastatic HER2-positive breast cancer that is resistant to trastuzumab, the addition of lapatinib to capecitabine improves progression-free survival and appears to lengthen overall survival. Furthermore, lapatinib has been studied in patients with involvement of the CNS and has been associated with stable disease and some responses. Its combination with letrozole provided an improvement in progression-free survival compared with single-agent letrozole in women with hormone receptor-positive, HER2-positive metastatic breast cancer. More recently, data suggested that the combination of lapatinib with trastuzumab significantly improves overall survival in women with metastatic breast cancer compared with single-agent lapatinib. Current indications in the USA for the use of lapatinib are for the treatment of metastatic HER2-positive breast cancer, both in combination with capecitabine in patients who have received taxane, anthracycline and traztuzumab, and in combination with letrozole for postmenopausal patients with hormone receptor- and HER2-overexpressing breast cancer. Common side effects of lapatinib include diarrhea and rash. Studies to date have found a less than 2% risk for cardiotoxicity, although most cardiac events that occurred during the studies were not attributed to lapatinib. It is important to consider that most of the patients in existing studies had already been treated with trastuzumab with no significant cardiotoxicity; therefore, future studies will show how trastuzumab-naive patients tolerate lapatinib. Ongoing research is evaluating the role of lapatinib in the adjuvant setting as a single agent or in combination with trastuzumab.
Lapatinib and breast cancer: current indications and outlook for the future.
Moreira C, Kaklamani V.
Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine of Northwestern University and the Robert H Lurie Comprehensive Cancer Center, 676 North St Clair Street, Suite 850, Chicago, IL 60611, USA.
Abstract
Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 (HER2) and blocks the EGF receptor. Studies have shown that in patients with metastatic HER2-positive breast cancer that is resistant to trastuzumab, the addition of lapatinib to capecitabine improves progression-free survival and appears to lengthen overall survival. Furthermore, lapatinib has been studied in patients with involvement of the CNS and has been associated with stable disease and some responses. Its combination with letrozole provided an improvement in progression-free survival compared with single-agent letrozole in women with hormone receptor-positive, HER2-positive metastatic breast cancer. More recently, data suggested that the combination of lapatinib with trastuzumab significantly improves overall survival in women with metastatic breast cancer compared with single-agent lapatinib. Current indications in the USA for the use of lapatinib are for the treatment of metastatic HER2-positive breast cancer, both in combination with capecitabine in patients who have received taxane, anthracycline and traztuzumab, and in combination with letrozole for postmenopausal patients with hormone receptor- and HER2-overexpressing breast cancer. Common side effects of lapatinib include diarrhea and rash. Studies to date have found a less than 2% risk for cardiotoxicity, although most cardiac events that occurred during the studies were not attributed to lapatinib. It is important to consider that most of the patients in existing studies had already been treated with trastuzumab with no significant cardiotoxicity; therefore, future studies will show how trastuzumab-naive patients tolerate lapatinib. Ongoing research is evaluating the role of lapatinib in the adjuvant setting as a single agent or in combination with trastuzumab.
AN INTERESTING STUDY
Leukemia. 2010 Aug 26. [Epub ahead of print]
Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies.
Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M, Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E.
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.
Abstract
We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were associated with lower response rates in RD (P=0.01), but not in VRD (P=0.219). The median progression-free survival (PFS) was similar for RD (9 months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor risk cytogenetics, especially del17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del17p remains extremely poor even with VRD combination.Leukemia advance online publication, 26 August 2010; doi:10.1038/leu.2010.175.
Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies.
Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M, Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E.
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.
Abstract
We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were associated with lower response rates in RD (P=0.01), but not in VRD (P=0.219). The median progression-free survival (PFS) was similar for RD (9 months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor risk cytogenetics, especially del17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del17p remains extremely poor even with VRD combination.Leukemia advance online publication, 26 August 2010; doi:10.1038/leu.2010.175.
A NEGATIVE GREEK STUDY!
Oncology. 2010 Aug 27;78(5-6):376-381. [Epub ahead of print]
Treatment of Colorectal Cancer with and without Bevacizumab: A Phase III Study.
Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A.
First Oncology Clinic, Errikos Dunant Hospital, Athens, Greece.
Abstract
Objective: The objective of this phase III trial was to compare chemotherapy combined with bevacizumab versus chemotherapy alone in the treatment of patients with advanced colorectal cancer. Methods: From September 2004 till September 2008, 222 treatment-naive patients were enrolled and divided into 2 arms: 114 arm A patients were treated with leucovorin, 5-fluorouracil plus irinotecan in combination with bevacizumab, and 108 arm B patients were treated as above without bevacizumab. All patients were stage IV with histologically confirmed adenocarcinoma. Results: The median overall survival of arm A patients was 22.0 months (95% CI: 18.1-25.9) and 25.0 months (CI: 18.1-31.9) for arm B patients. There was no statistically significant difference between the 2 arms (p = 0.1391). No statistically significant difference between the 2 arms regarding the response ratewas observed: partial response, 42 patients (36.8%) and 38 patients (35.2%) for arms A and B, respectively. Hematologic toxicity did not differ in the comparison of the 2 arms. Nonhematologic toxicity in arm A involved hypertension in 23 (20.2%) of the patients and proteinuria in 7 (6.1%); 3 patients experienced hemorrhage and 1 patient intestinal perforation. None of these side effects was observed in arm B patients. Conclusion: No statistically significant difference in median overall survival in patients with advanced colorectal cancer treated with bevacizumab plus a combination therapy (arm A) and those treated with the combination only, without bevacizumab (arm B), was observed.
Treatment of Colorectal Cancer with and without Bevacizumab: A Phase III Study.
Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A.
First Oncology Clinic, Errikos Dunant Hospital, Athens, Greece.
Abstract
Objective: The objective of this phase III trial was to compare chemotherapy combined with bevacizumab versus chemotherapy alone in the treatment of patients with advanced colorectal cancer. Methods: From September 2004 till September 2008, 222 treatment-naive patients were enrolled and divided into 2 arms: 114 arm A patients were treated with leucovorin, 5-fluorouracil plus irinotecan in combination with bevacizumab, and 108 arm B patients were treated as above without bevacizumab. All patients were stage IV with histologically confirmed adenocarcinoma. Results: The median overall survival of arm A patients was 22.0 months (95% CI: 18.1-25.9) and 25.0 months (CI: 18.1-31.9) for arm B patients. There was no statistically significant difference between the 2 arms (p = 0.1391). No statistically significant difference between the 2 arms regarding the response ratewas observed: partial response, 42 patients (36.8%) and 38 patients (35.2%) for arms A and B, respectively. Hematologic toxicity did not differ in the comparison of the 2 arms. Nonhematologic toxicity in arm A involved hypertension in 23 (20.2%) of the patients and proteinuria in 7 (6.1%); 3 patients experienced hemorrhage and 1 patient intestinal perforation. None of these side effects was observed in arm B patients. Conclusion: No statistically significant difference in median overall survival in patients with advanced colorectal cancer treated with bevacizumab plus a combination therapy (arm A) and those treated with the combination only, without bevacizumab (arm B), was observed.
GEMCITABINE-CARBOPLATIN MECHANISM OF SYNERGY
Clin Cancer Res. 2010 Aug 18. [Epub ahead of print]
Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for 'platinum-resistant' ovarian cancer.
Ledermann JA, Gabra H, Jayson GC, Spanswick VJ, Rustin GJ, Jitlal M, James L, Hartley JA.
UCL Cancer Institute, University College London.
Abstract
BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in 'platinum-resistant' ovarian cancer. Peripheral blood lymphocytes (PBLs) were sampled after drug administration to measure DNA interstrand crosslink formation and repair.
PATIENTS AND METHODS: 40 patients received carboplatin AUC4 followed by gemcitabine 1000 mg/m2 with a second dose of gemcitabine on day 8. PBLs were obtained in 12 patients before, and at intervals during the first cycle of chemotherapy. DNA crosslink formation and repair (unhooking) were measured by the single cell gel electrophoresis (comet) assay following ex vivo incubation.
RESULTS: The global response rate was 47% (RECIST rate: 29%; CA125 rate: 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA crosslinking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA crosslinks following administration of gemcitabine.
CONCLUSION: An enhanced activity of carboplatin in 'platinum-resistant' ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA crosslinks. Future studies should explore co-administration of these drugs, as this may be a more effective schedule.
Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for 'platinum-resistant' ovarian cancer.
Ledermann JA, Gabra H, Jayson GC, Spanswick VJ, Rustin GJ, Jitlal M, James L, Hartley JA.
UCL Cancer Institute, University College London.
Abstract
BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in 'platinum-resistant' ovarian cancer. Peripheral blood lymphocytes (PBLs) were sampled after drug administration to measure DNA interstrand crosslink formation and repair.
PATIENTS AND METHODS: 40 patients received carboplatin AUC4 followed by gemcitabine 1000 mg/m2 with a second dose of gemcitabine on day 8. PBLs were obtained in 12 patients before, and at intervals during the first cycle of chemotherapy. DNA crosslink formation and repair (unhooking) were measured by the single cell gel electrophoresis (comet) assay following ex vivo incubation.
RESULTS: The global response rate was 47% (RECIST rate: 29%; CA125 rate: 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA crosslinking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA crosslinks following administration of gemcitabine.
CONCLUSION: An enhanced activity of carboplatin in 'platinum-resistant' ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA crosslinks. Future studies should explore co-administration of these drugs, as this may be a more effective schedule.
CHEMOTHERAPY FOR SARCOMATOID RENAL CANCER
Med Oncol. 2010 Aug 18. [Epub ahead of print]
Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy.
Dutcher JP, Nanus D.
Oncology, New York Medical College, Montefiore, North Division, 600 East 233rd Street, Bronx, NY, 10466, USA, jpd4401@aol.com.
Abstract
Sarcomatoid renal cell cancer is associated with a very poor prognosis, characterized by rapid progression of advanced disease. We previously reported the outcome of 18 patients with advanced sarcomatoid renal cell cancer treated with a regimen consisting of doxorubicin, 50 mg/m(2) and gemcitabine, 1,500-2,000 mg/m(2), administered every two weeks with growth factor support (A/G). Among the 18 patients, there were two complete and 5 partial responses and two patients with stable disease of more than 6 months of duration. We now report long-term survival of 4 patients with stage IV sarcomatoid renal cell carcinoma treated with this regimen at the 1,500 mg/m(2) dose of gemcitabine, and achieving complete response (2 patients), or rendered complete responders following surgery after maximum response (2 patients). The two complete responders are alive, disease free at 6+ and 8+ years after starting A/G, and the 2 patients rendered CR by surgery survived 3(1/2) and 6 years, respectively. Both died of progressive disease, one with clear cell recurrence, one with sarcomatoid recurrence. In summary, this regimen is associated with a high response rate, overall improvement in progression free survival and occasional meaningful long-term survival in a disease expected to be fatal within one year.
Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy.
Dutcher JP, Nanus D.
Oncology, New York Medical College, Montefiore, North Division, 600 East 233rd Street, Bronx, NY, 10466, USA, jpd4401@aol.com.
Abstract
Sarcomatoid renal cell cancer is associated with a very poor prognosis, characterized by rapid progression of advanced disease. We previously reported the outcome of 18 patients with advanced sarcomatoid renal cell cancer treated with a regimen consisting of doxorubicin, 50 mg/m(2) and gemcitabine, 1,500-2,000 mg/m(2), administered every two weeks with growth factor support (A/G). Among the 18 patients, there were two complete and 5 partial responses and two patients with stable disease of more than 6 months of duration. We now report long-term survival of 4 patients with stage IV sarcomatoid renal cell carcinoma treated with this regimen at the 1,500 mg/m(2) dose of gemcitabine, and achieving complete response (2 patients), or rendered complete responders following surgery after maximum response (2 patients). The two complete responders are alive, disease free at 6+ and 8+ years after starting A/G, and the 2 patients rendered CR by surgery survived 3(1/2) and 6 years, respectively. Both died of progressive disease, one with clear cell recurrence, one with sarcomatoid recurrence. In summary, this regimen is associated with a high response rate, overall improvement in progression free survival and occasional meaningful long-term survival in a disease expected to be fatal within one year.
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