Journal of the National Cancer Institute Advance Access originally published online on June 10, 2008
JNCI Journal of the National Cancer Institute 2008 100(12):836-844; doi:10.1093/jnci/djn200
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© Oxford University Press 2008.
NEWS |
Breast Cancer Testing Scandal Shines Spotlight on Black Box of Clinical Laboratory Testing
A Canadian public inquiry into botched estrogen receptor tests has shaken public confidence in cancer care and raised questions about the oversight of laboratories that perform crucial tests that often determine which treatment breast cancer patients receive. The public inquiry, now under way in Newfoundland, is charged with investigating events that led to a breakdown of estrogen receptor (ER) testing at a laboratory run by Eastern Health, the provincial health care delivery system in Newfoundland and Labrador. Through the inquiry, the public learned that between 1997 and 2005 nearly 400 of about 1,000 breast cancer patients received incorrect test results of the ER status of their breast tumors. Of these patients, more than 100 have since died, leaving grieving families wondering if inaccurate test results cost their loved ones’ lives.
Nearly every newly diagnosed breast cancer tumor is tested to determine its ER status. Patients whose tumors test ER positive often receive hormonal therapies such as tamoxifen, which is effective against ER-bearing tumors. Incorrect ER tests can result in ineffective treatment being given to patients, or conversely, effective treatment being withheld.
The problems first came to light in 2005 when physicians began questioning the ER test results of a patient diagnosed with invasive lobular carcinoma. The patient's results were negative, but typically this form of breast cancer is ER positive. Retesting showed that the initial test result was wrong. An internal investigation by Eastern Health led to more than 1,000 patients’ tumors being retested at a laboratory in Ontario. The high error rate was not widely acknowledged, and often, even the affected patients were not told the retest results, according to testimony given at the inquiry. A commission led by the Honorable Margaret A. Cameron will report the conclusions of the inquiry and will make recommendations for systemic change at the laboratory in July. Separately, more than 200 patients affected by the ER test are participating in a class-action lawsuit against Eastern Health.
An investigative article on the retesting published in the St. John's Independent, a weekly newspaper, sparked public outrage and eventually led to the inquiry, which has revealed overworked pathologists and a lack of standards at the Newfoundland laboratory that also raise troubling questions about working conditions at clinical laboratories not just in Canada but also in the United States.
A chronic shortage of trained pathologists in Canada has led to work overload and high employee turnover in Newfoundland and elsewhere in Canada. "Keeping pathologists in the province [Newfoundland] has been a dismal task," said Nebojsa (Nash) Denic, M.D., Ph.D., chief of laboratory medicine at St. Clare's Hospital, the Eastern Health facility where the ER testing was conducted. "It has been a revolving door for so many years. In the last 10 years, out of 19 positions that we have, those positions have been occupied by 36 pathologists."
Many positions are being filled by foreign-trained pathologists who often work for years without certification by the Royal College of Physicians and Surgeons, Denic said.
Although Canada has a national health care system, health care delivery is handled regionally, with each province operating by its own standards. For example, Newfoundland has no regulatory body that accredits or sets standards for conduct of clinical laboratory tests, whereas Ontario has strict laboratory accreditation requirements. Similarly, in the United States clinical laboratories are regulated on a state-by-state basis, with only 12 states requiring certification of laboratory personnel. The only federal U.S. standard is the Clinical Laboratory Improvement Amendments of 1988, which set a minimum standard of compliance but does not require professional certification for laboratories or their personnel.
"There is really no way of knowing who is working and what their credentials are," said Elissa Passiment, executive director of the American Society for Clinical Laboratory Science (ASCLS). "People in the laboratory can be anyone. ASCLS spends a great deal of time trying to get the federal government and state governments to understand that it is a mistake not to have some kind of quality assurance as far as personnel are concerned."
Also, many of the senior leadership of clinical laboratories were trained before the emergence of the sophisticated molecular tests that are now key diagnostic tools that often determine the course of treatment for cancers such as those of the breast, colon, or prostate. According to the College of American Pathologists (CAP), the average age of the approximately 23,000 board-certified pathologists in the United States is between 50 and 55 years.
"It's a serious issue of continuing education," said Elizabeth Hammond, M.D., professor of pathology at the University of Utah and member of the education committee for CAP. "Very few pathologists have adequate training in molecular pathology, and almost no one understands that it is critical to use standardized methods in interpretation and reporting for these kinds of tests like ER, PR [progesterone receptor], and HER2 [human epidermal growth factor receptor 2] in breast cancer."
Slow Changes
Within Canada, public reaction to the ER testing controversy has motivated Canadian professional medical associations to push for systemic changes in medical training and laboratory staffing, but some physicians working for reform worry that change will come slowly.
"It is an aspirational goal of the Royal College to restore Royal College certification as the only means of being registered as a specialist and licensed in one of Canada's 10 provinces," said Andrew Padmos, M.D., chief executive officer of the Royal College of Physicians and Surgeons. "The sad reality is that each province makes its own decisions on licensing and recognizing specialties, and so the smaller ones who feel they don’t have the money or the facilities to compete for the limited supply of Canadian-trained physicians feel like they have to go to an international marketplace to get the jobs filled by anybody at all."
The Royal College is now leading a group of seven participating medical societies in Canada to examine the underlying deficiencies that led to the ER testing errors and to make recommendations to each provincial health minister that address the widespread deficiencies in medical staffing that Padmos said are systemwide. For example, a 2007 report commissioned by the Newfoundland and Labrador Health Department cited a 32% turnover rate for the Atlantic province over the previous 4 years.
"Right now what happens is people cover their heads and say, ‘Oh yes, that's a problem in Newfoundland or New Brunswick, and they are far, far away. It couldn’t happen here,’" he said. "Our understanding is that it could happen many places. The shortages are widespread in Canada ... and the safety net that we operate with really has some significant holes in it."
Some have also been warning that an aging population of pathologists and fewer newly minted doctors choosing pathology will soon create significant shortages in the United States as well. The problem is that no group tracks trends in hiring or unfilled positions, leading to disagreement about whether there really is a shortage.
"From data that we have at the CAP, when people are retiring, we are not replacing them," said Jared Schwartz, M.D., Ph.D., director of pathology and laboratory medicine at Presbyterian Healthcare in Charlotte, N.C., and president of CAP. "If you talk to the young people who are coming out of training, most of them have two, three, four, five job offers."
The situation isn't dire yet, he added, but with the advent of molecular tools, the need for trained pathologists in the oncology arena is greater than ever, as is adequate oversight of laboratories that perform these crucial tests. CAP audits and accredits laboratories that perform complex procedures such as immunohistochemistry and fluorescence in situ hybridization, which are used in testing for ER status and for the presence of HER2 in breast tumor samples. However, such certification is not required, and no organization keeps track of how many labs perform these procedures or whether the technicians who perform the tests are properly trained.
Creating Greater Accountability
For oncologists who rely on such test results to make treatment decisions, the black box of clinical laboratory testing creates a substantial problem for patient and physician alike. "There are no good data on the quality of ER testing in the United States," said Craig Allred, M.D., director of breast pathology at Washington University School of Medicine in St. Louis. "The scary thing about the debacle in Canada is that we would never have known about this if results hadn’t been checked in a central lab."
The difficulty with ER testing, Schwartz said, is that even large, well-regarded institutions have different procedures and criteria for determining ER status.
"Especially for oncologists in private practice, who may not work in one hospital, who may have patients who have surgery and biopsies in various places, they have absolutely no way that they can, on their own, figure out exactly if a lab is using a validated assay or not," said Antonio Wolff, M.D., associate professor of oncology at Sidney Kimmel Cancer Center in Baltimore.
However, Wolff acknowledged that there is a growing concern about quality assurance in laboratories that perform oncology testing. In response to calls for greater accountability, CAP and the American Society of Clinical Oncology have teamed up to develop guidelines and required certification for labs that perform complex oncology testing procedures, claiming authority under the 1988 Clinical Laboratory Improvement Amendments. The first set of guidelines, published simultaneously in the January 2007 issues of the Journal of Clinical Oncology and the Archives of Pathology and Laboratory Medicine, lay out a framework for HER2 testing.
Also, the guideline "strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment."
The CAP laboratory accreditation program now requires that every CAP-accredited laboratory performing HER2 testing conform to the standards laid out in the guidelines. The CAP program will also ensure that required proficiency testing takes place and performance below 90% will be considered unsatisfactory.
Hammond, who served on the HER2 guideline committee, along with Wolff, Allred, and Schwartz, said that inspectors for the program are now being trained and that as inspections begin, laboratories will either come into compliance or get out of the HER2 testing business. "We don’t know what the number is of laboratories doing HER2 testing," Hammond said. "But because of the guideline coming out I strongly suspect that the number of laboratories is going to be declining."
Hammond said that the group is poised to begin work on guidelines for ER testing that should be published by mid-2009. She acknowledged that there is an increased sense of urgency surrounding the task with news of the Canadian testing errors.
"It's a complex problem that involves other aspects like fixation and specimen handling," said Hammond. "We have those problems in the United States too, but until we start doing this guideline, we aren't going to know exactly what we are up against."
Fallout
Within Canada, the failure of ER testing in Newfoundland has caused a crisis in confidence in the cancer care system, said Peter Dawe, executive director of the Canadian Cancer Society's Newfoundland/Labrador branch. He said that the organization has set up a phone line for patients who are concerned about their test results.
Many who have called are patients with other types of cancer who are not directly affected by the ER testing but are still afraid that they may also have been given incorrect test results, he said.
"In my mind, this is an issue that comes back starkly to the professionals involved," Dawe said. "As far as a professional practice issue for pathologists, ultimately it rests there. If they want to be self-regulated, then they should make sure they have their own best practices in place. But given the history, and if that's not going to happen, you have to find either at the provincial or the national level the leverage to get at these standards-of-care issues. From a Cancer Society perspective, certainly in Newfoundland and Labrador, we are not going to let go of it until we keep pushing it through."
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