Study is first solid evidence that introduction of HPV vaccines may be a factor in the reduction in rates of cervical cancer among those who were vaccinated nearly 20 years ago
This success story confirms that a better understanding of what causes cervical cancer—when combined with the development of clinical laboratory tests that detect the HPV virus—were key developments in the fight against this deadly disease.
The study, led by cancer population scientist Ashish Deshmukh, PhD, epidemiologist, professor of public health sciences and co-leader of the cancer control program at the Hollings Cancer Center (HCC) at MUSC, found the connection between the decline in cervical cancer rates and the adoption of the HPV vaccine.
Pathologists and clinical laboratory managers will want to monitor the worldwide effort to eradicate cervical cancer, as many countries focus their efforts on HPV vaccine compliance. The scientists published their findings in the Journal of the American Medical Association (JAMA) titled, “Cervical Cancer Mortality among US Women Younger than 25 Years, 1992-2021.”
“We had a hypothesis that since it’s been almost 16 years, that maybe we might be starting to see [the] initial impact of HPV vaccination on cervical cancer deaths, and that’s exactly what we observed,” Ashish Deshmukh PhD (above), epidemiologist and professor of public health sciences at Medical University of South Carolina in Charleston, told Science News. The MUSC study provides important findings for clinical laboratories and anatomic pathologists providing vaccinations against Human Papillomavirus. (Photo copyright: Medical University of South Carolina.)
MUSC Study Details
Deshmukh’s team examined cervical cancer mortality rates of women younger than 25 from 1992-2021. The team divided data into 3-year periods, noting a “gradual decline in cervical cancer deaths of almost 4%” which brought deaths to .02 per 100,000 people from 2013-2015, Science News reported, adding that the researchers speculated that the “steady drop might be due to improved prior prevention and screening methods for cervical cancer.”
The death rate for cervical cancer continued to trend downward with “a dramatic reduction in mortality over just 60%,” arriving at .007 deaths per 100,000 according to the 2019-2021 data, Science News continued.
In their JAMA article, the MUSC researchers noted a continued positive shift toward lower cervical cancer rates beyond 2021, with a 12% per year decline and 65% reduction overall.
“They’re seeing this precipitous drop in mortality at the time that we would be expecting to see it due to vaccination,” Emily Burger, PhD, professor at the University of Oslo and research scientist at Harvard T.H. Chan School of Public Health told Science News. “Ultimately, we hope we are preventing mortality and death [with the introduction of vaccines], and this study is really supporting that conclusion.”
Nonetheless, a definitive connection to the HPV vaccine was not possible to determine “because it’s unclear whether the women in the study cohort were, in fact, vaccinated,” Science News reported.
Development of the PAP Smear
Cervical cancer was first discovered in 1886. At that time pathologists relied on “examination of tissue biopsies derived from an observable lesion,” LabTAG noted. It was George Papanicolaou, PhD—considered to be the father of cytology—who determined in 1943 that more could be observed via a surface biopsy under a microscope. The Pap Smear was born.
The Pap Smear, for which wider screening began in the US in the late 1950s and 1960s, began to reduce deaths from cervical cancer by the 1990s. But women who did not get an annual pap were the ones generally to be diagnosed with advanced cervical cancer.
By the 1990s, pap smear testing was a major business for clinical laboratories and pathology groups. Fifty-five million pap tests were done annually in the 1990s.
In 2004, clinical laboratories began HPV testing. Then came the HPV vaccine. Introduced in 2006, HPV vaccine programs focused on 12-15 year-old girls with hopes of preventing cervical cancer.
Clinical laboratories in the US today perform many fewer Pap smear tests.
While efforts overseas appear to focus on HPV vaccine requirements, the US has been hesitant to do the same. The District of Columbia, Hawaii, Virginia, and Rhode Island are the only states to require it by grade seven, Immunize.org notes. Various reasons have kept it from being required in the US, including fear that it might encourage sexual activity in teens.
There is hope that, with a larger focus on cervical cancer, more deaths can be prevented since the cancer itself is slow growing. “When we look at HPV vaccination coverage in the US, we haven’t reached our goal. We have to do better in terms of improving vaccination rates,” Deshmukh told Science News.
As scientists continue to gain a better understanding of causes and prevention of cervical cancer, new clinical laboratory tests may be developed to detect HPV. Thus, lab managers will want to stay in touch with current research as it will surely impact the testing performed by labs in the future.
Proof-of-concept study may eventually lead to new clinical laboratory urine tests for fast, non-invasive detection of cancer
Here is the latest example of researchers finding useful biomarkers in urine for diagnosing certain cancers. The discovery comes from the University of Michigan Health Rogel Cancer Center, where, in a proof-of-concept study, scientists developed a urine-based test that screens for circulating free DNA (cfDNA) fragments (aka, cell-free DNA) released by tumors in the head and neck. If they confirm these findings, it’s possible the technology could be adapted into a non-invasive clinical laboratory test for selected cancers.
One such cancer is human papillomavirus (HPV) which, though “widely recognized for causing cervical cancer” is “increasingly found to cause cancers in the mouth, throat, and other head and neck regions,” according to a U-M Medical School press release.
The U-M study findings could lead to an early, non-invasive test for the detection of cancer, as compared to traditional urine or blood-based liquid biopsy testing.
“In this study, we provide evidence to support the hypothesis that conventional assays do not detect ultrashort fragments found in urine since they are designed to support longer DNA fragments. Our team used an unconventional approach to develop a urine test for HPV-positive head and neck cancer ctDNA detection,” said Chandan Bhambhani, PhD (above), Research Lab Specialist Intermediate at University of Michigan and co-first author of the study, in a news release. Clinical laboratories may soon have a new urine-based test for detecting cancer. (Photo copyright: LinkedIn.)
According to the researchers, benefits of urine testing include:
Testing with urine is convenient for people who may be unable to access healthcare and phlebotomy services.
Urine has low biohazard risk and may be easily collected in large amounts, compared with blood.
Ongoing collection of urine could make way for TR-ctDNA “kinetics to be used as a high time-resolution biomarker” to monitor patients’ response to treatment.
However, urine, the researchers cautioned, must be analyzed in a different manner if it is to be comparable in efficiency to blood-based ctDNA testing.
“There have been mixed reports on the efficiency of TR-ctDNA detection compared with that of blood ctDNA. A potentially crucial factor for the analysis of TR-ctDNA is knowing the length of TR-ctDNA fragments present in urine, because this affects assay design for optimal sensitivity in TR-ctDNA detection,” the researchers explained.
New Assay Detects Ultrashort DNA Fragments
To complete their study, the U-M researchers developed an ultrashort HPV droplet digital PCR (polymerase chain reaction) assay that enabled detection of TR-ctDNA from HPV-associated oropharyngeal squamous cell carcinoma (HPV OPSCC), BioTechniques reported.
The assay was made to target the HPV16 E6 (Human papillomavirus 16) gene and to measure TR-ctDNA in patients with HPV OPSCC, the JCI Insight paper noted.
“The HPV16 E6 gene represents a highly recurrent ctDNA target in the population of patients with HPV OPSCC,” the researchers wrote in JCI Insight, adding:
Targeting ultrashort fragments was essential “for robust TR-ctDNA detection.”
Results in urine with patients with HPV OPSCC was consistent with results from plasma ctDNA.
The test, still in the discovery phase, was mailed to patients who were being treated for the disease and who reside within 100 miles of Ann Arbor, Mich. They returned urine samples for testing at the U-M lab and to get insights into possible post-treatment needs.
“Using longitudinal urine samples from a small case series, we showed proof of concept for early detection of cancer recurrence. Thus, our results indicate that by targeting ultrashort DNA fragments, TR-ctDNA becomes a viable approach for HPV OPSCC detection and potentially for cancer recurrence monitoring after treatment,” the authors wrote.
Further Studies, Possible Test Expansion
HPV infection—and especially HPV type 16—is a growing risk factor for oropharyngeal cancers, according to the National Cancer Institute.
The U-M Rogel Cancer Center scientists plan more studies to leverage the information urine may carry about an individual’s health. The researchers intend to expand the scope of their new test to other cancers including breast cancer and acute myeloid leukemia.
“The test that has been developed has detected cancer far earlier than would typically happen based on clinical imaging. As such, these promising results have given us the confidence to broaden the scope of this study, seeking to expanding distribution even further,” said J. Chad Brenner, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery, U-M Medicine, and co-senior author of the study, in the news release.
The University of Michigan Health study exemplifies scientists’ commitment to new categories of biomarkers that can be used for medical laboratory tests and prescription drugs. And by focusing on urine, the researchers made it possible for patients to collect specimens themselves and send them to the medical laboratory for analysis and reporting.
Some experts question the usefulness of Pap testing going forward. But how would cutting back on Pap testing affect clinical laboratory revenue and is it safe for cancer patients?
Recently, a major medical society issued its findings that cervical cancer in the United States has been on a sustained decline for more than a decade and a half. This confirms what cytopathologists and cytotechnologists have watched as the development of new clinical laboratory tests, and the introduction of a vaccine for HPV (human papillomavirus) about 15 years ago, contributed to a reduction in the number of cervical cancer deaths annually here in the United States and in several other nations.
As incidences of cervical cancer declined, so have orders for Pap tests. Thus, clinical laboratory revenues in this area also have declined. This is a change from the 1990s and early 2000s, when Pap tests were the primary screening tool for cervical cancer. About 55 million Pap tests were performed annually during those years and many labs maintained sizeable numbers of cytotechs to perform these tests.
HPV Testing Drove Decreases in Cervical Cancer, Decline in Pap Testing
For at least the past decade, there are pathologists, cytotechnologists, and medical laboratory scientists who graduated from their training programs and began working in labs unaware that, since the 1990s, conventional Pap testing as a major source of test referrals and revenue for clinical laboratories and pathology groups has been on the decline.
What is the reason for the decline? Advances in several areas of medicine, implemented over the past 25 years, have greatly altered how we screen for cervical cancer today. And, in a stepwise fashion, the HPV test and HPV vaccine steadily reduced the role of Pap tests as a primary screening tool.
HPV, a common sexually-transmitted virus, is linked to not only cervical cancer, but also cancers of the vulva, vagina, penis, and anus, according to the Centers for Disease Control and Prevention (CDC) data, which recorded 43 million HPV infections in the US in 2018.
“It is likely that the significant decrease in cervical cancer incidence (in the US) results from clear guidelines for cervical cancer screening and may also reflect promotion and acceptance of [HPV] vaccination, particularly in younger women,” said the ASCO study’s lead author Cheng-I Liao, MD (above), in a news release. Liao is affiliated with Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. (Photo copyright: Healio.)
Cervical Cancer Down, But Other HPV Cancers Up
Though cervical cancer incidence is down, other HPV-related cancers may need additional screening standards to head off rising cancer cases, the ASCO study suggests.
To conduct their study, the ASCO researchers analyzed data for 657,317 people in the US Cancer Statistics (USCS) program from 2001 to 2017. The researchers reported their findings at the 2021 ASCO Annual Meeting held online in June. They include:
Cervical cancer incidence rate decreased each year by 1.03% annually over 16 years.
In the 20 to 24 age group, a “disproportionately higher decrease” of 4.6% per year in cervical cancer incidence rate suggested “potential effect of vaccinations.”
Without screenings, HPV-related cancers incidence increased in women over 16 years.
Oropharyngeal, anal, rectal, and vulvar cancer increased 1.3% in women per year.
In men, oropharyngeal cancer incidence represented 81% of all HPV-related cancers—five times more than cases for women over 16 years.
HPV-related cancers in men increased 2.36% per year over 16 years, and oropharyngeal cancer had the biggest increase.
“Without standardized screening, HPV-related cancers—such as oropharyngeal cancers and anal rectal cancers—are increasing. To reduce these trends and achieve success comparable to what we’re seeing with cervical cancer we must develop effective screening strategies and determine vaccine efficacy in these patient populations,” Liao said in the news release.
Should PAP Tests Be Dropped as a Primary Screen for Cervical Cancer?
Today’s American Cancer Society (ACS) guidelines for cervical cancer screening denote the primary (FDA-designated) HPV test as the “preferred test” for people 25 to 65 years of age. A Pap test (or Pap smear) can be done at the same time, or in instances when a primary HPV test is not available, the ACS said.
HPV screening aims to detect high risk strains of HPV by looking for DNA in cervical cells and the Pap test involves collecting cells from the cervix for review in the medical laboratory for cancer and pre-cancer, the ACS added.
However, pathologists and cytotechnologists who have examined Pap smear slides for many years know that indications of cervical cancer are not always detected by HPV screening. A Pap test often picks up indications of cervical cancer that might not have been detected by the HPV test.
One reason is HPV tests only monitor about 20 of the genetic mutations known to cause cervical cancer. There are about 80 mutations that can cause cervical cancer, but most are so rare, it does not pay to include them in the HPV test panel.
“The Pap is not something that we should look at as replaceable. In some circumstances, we can get a Pap smear that has some significant cellular changes on it,” Jessica Shepherd, MD, an obstetrician and gynecologist at Baylor University Medical Center in Dallas, told USA Today.
Medicine Advancing, Pap Referrals Not So Much
In the 1990s, Pap tests were the front line for cervical cancer screening and a source of about 55 million referrals to clinical laboratories each year, recalls Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
“Interestingly, in the past decade, many cytotechnologists and laboratory scientists who started work in labs at the time of the new HPV screening guidelines and vaccination were unaware of the Pap test’s impact on revenue for clinical labs and pathology groups,” he said.
Medical advancements over the past 25 years have altered how providers screen women for cervical cancer and help them prevent it. And as HPV screening and HPV vaccination gained prominence, the standard Pap test became a kind of “co-pilot” to HPV testing. Unfortunately, this meant less oncology referrals to medical labs.
COPD and gestational diabetes research are the subject of two new projects aimed at intercepting diseases prior to onset and identifying preventive treatments
Can new insights into the human genome make it possible to diagnose disease much earlier—even before symptoms can be observed? Multiple research programs are targeting this possibility. One example is being conducted by Johnson & Johnson (J&J). The American multinational medical-device company wants to leverage recent developments in genetics, data analysis, and its worldwide partnerships, in an attempt to answer two profound questions:
• Can the earliest signals of disease be identified; and
• What treatments will assist researchers who are trying to prevent diseases?
To pursue these two goals, Johnson & Johnson (NYSE: JNJ) is expanding its existing research project into disease prediction and prevention, which currently involves 24 global partners, according to an Associated Press March story. (more…)
