Cervical Squamous Cell Carcinoma

BRONX, N.Y., Sept. 7, 2023 /PRNewswire/ -- In findings with potentially important implications for cervical cancer screening, scientists at the National Cancer Institute (NCI)-designated Montefiore Einstein Cancer Center (MECC) have developed a test for detecting a type of cervical cancer that Pap tests often miss. The findings published online today in the Journal of the National Cancer Institute (JNCI). "Our novel test appears sensitive for detecting cervical adenocarcinoma [ADC]—which now accounts for up to 25% of cervical cancer cases—as well as its precursor lesions, adenocarcinoma in situ [AIS], that often develop into ADCs," said Howard Strickler, M.D., M.P.H., co-senior and corresponding author of the JNCI paper and a member of MECC. "Because ADCs are often missed by current screening methods, they have higher mortality rates than the more common cervical squamous cell cancer," Dr. Strickler added. "Our goal is to catch the disease early, before it develops into cancer." Dr. Strickler is also professor and head of the division of epidemiology and the Harold and Muriel Block Chair in Epidemiology and Population Health at Albert Einstein College of Medicine. A Novel Approach to Testing The widespread use of the Pap test, in which a pathologist examines tissue samples for abnormal cells, has significantly reduced the incidence of cervical squamous cell cancer over the past six decades. However, the incidence of ADC has not decreased, probably because the Pap test is less effective at detecting it. In recent years, testing for human papillomaviruses (HPVs)—which cause virtually all cases of cervical cancer—joined the Pap test as a standard screening tool for cervical cancer. Although there are more than 100 types of HPV, three types—HPV 16, 18, and 45—account for more than 70% of all cervical cancer cases and more than 90% of ADC cases. The current HPV tests cover all three types and can alert infected women that they face a high risk for developing cervical cancer. While vaccines for preventing cervical cancer—including Gardasil-9, which protects against nine HPV types—are safe and effective, several generations of women are above the age for receiving the vaccine. Therefore, screening and treatment for prevention of cervical cancer will remain critical for decades to come. The MECC-developed HPV test assessed HPV 16, 18, and 45 in a novel way: by specifically looking at methylation levels. "The advent of next-generation genetic testing has opened up opportunities for us to more accurately detect oncogenic HPV strains and patterns in the genomes that correspond with the development of AIS and ADC," said Robert D. Burk, M.D., professor of pediatrics, of microbiology & immunology, of epidemiology and population health, and of obstetrics & gynecology and women's health at Einstein and MECC member, who co-led the study. Methylation—the addition of methyl (CH3) groups to a region of DNA—is a routine occurrence in DNA, both viral and human, and plays a critical role in altering gene expression. The JNCI study, a collaborative project with the NCI, part of the National Institutes of Health, investigated methylation levels in cervical tissue samples from 1,400 women who had undergone cervical cancer screening at Kaiser Permanente Northern California before 2014 and whose cervical cancer status was known. In assessing the HPVs in the cytological samples, the researchers tallied up the methylation percentages for each of 35 different viral-genome sites, with each sample receiving a final "methylation score" equal to the average methylation percentage across all 35 sites. Those women with methylation scores in the upper 25% had very high odds for having developed either ADC or AIS. "Our findings, if confirmed by clinical trials, suggest that women with a high methylation score may benefit from colposcopy and specialized tissue evaluation, beyond just a Pap test, which could lead to early diagnosis and treatment for ADC or the removal of AIS lesions before they develop into ADC," said Dr. Burk. Improving Equity in Cervical Cancer Screening "Given that our test uses equipment that could be simplified, it has the potential to expand testing in lower-resourced countries," said Dr. Strickler, who has long studied HPV in women living with HIV, who are more likely to acquire an HPV infection. Cervical cancer remains the fourth most common type of cancer in women, with the burden significantly higher in lower- and middle-income countries, including those in Sub-Saharan Africa, where HIV-HPV coinfections are common. There are also significant disparities within the United States. In New York City, rates of cervical cancer in the Bronx, which is home to the poorest urban congressional district in the country, are 50% higher than in Manhattan. More frequent and effective screening could help address this health disparity. "Ideally, the new HPV methylation test would only need to be done once every three to five years," said Dr. Strickler. "We are hopeful that this test will be able to increase cervical cancer screening equity in the U.S. as well." The paper is titled "A Novel HPV/Host DNA Methylation-Score and Detection of Cervical Adenocarcinoma." In addition to Drs. Strickler and Burk, other Einstein authors on the study were Ana Gradissimo, Ph.D., Xiaonan Xue, Ph.D., and Philip E. Castle, Ph.D, M.P.H. (also affiliated with the NCI). Other contributors were Megan A. Clarke, Ph.D., M.H.S., Mark Schiffman, M.D., M.P.H., and Nicolas Wentzensen, M.D., Ph.D., M.PH., all at NCI, and Tina R. Raine-Bennett, M.D., M.P.H. at Kaiser Permanente. About Montefiore Einstein Cancer Center Montefiore Einstein Cancer Center (MECC) is a national leader in cancer research and care located in the ethnically diverse and economically disadvantaged borough of the Bronx, N.Y. MECC combines the exceptional science of Albert Einstein College of Medicine with the multidisciplinary and team-based approach to cancer care of Montefiore Health System. Founded in 1971 and a National Cancer Institute (NCI)-designated Cancer Center since 1972, MECC is redefining excellence in cancer research, clinical care, education and training, and community outreach and engagement. Its mission is to reduce the burden of cancer for all, especially people from historically marginalized communities. SOURCE Montefiore Einstein Cancer Center

Patients with head and neck cancer who have more genetic material on chromosome 9 in their cancer cells survive three times longer after receiving immunotherapy than those with less genetic material there. Patients with head and neck cancer who have more genetic material on chromosome 9 in their cancer cells survive three times longer after receiving immunotherapy than those with less genetic material there, a new study finds. Within both normal and cancerous cells, chromosomes are the 23 superstructures that house, organize, and protect the DNA code. Led by researchers from NYU Grossman School of Medicine and UC San Diego Moores Cancer Center, the new study revolves around the human immune system, which can recognize cancer cells as abnormal and attack them. Cancer cells hide from the system by hijacking "checkpoint" sensors that keep the immune cells from attacking normal cells. As a leading immunotherapy class, checkpoint inhibitors use proteins called antibodies to make tumors "visible" again. For head and neck cancer, however, only about 15 percent of patients respond well to immune checkpoint blockade, say the study authors. Antibodies only work if there are enough immune cells present to notice them, a state called "immune hot," with the field understanding little about why so many patients have too few immune cells near their immune cold tumors. Specifically the study addresses HPV-negative head and neck squamous-cell (HNSC-HPVneg) carcinomas, the most common and lethal subtype of head and neck cancer with more 200,000 deaths globally per year. Published online the week of November 14 in the Proceedings of the National Academy of Sciences (PNAS), the study found that HNSC-HPVneg cancer patients with a greater supply in their cancer cells of a region on chromosome 9 called 9p24.1 live 30 months on average after checkpoint inhibitor treatment, while those with lower amounts of it survive for 11 months on average. "These findings reveal 9p24.1 as a genetically defined axis that promises to determine for the first time whether HNSC patients will do well or poorly on a checkpoint inhibitor," says co-senior study author Teresa Davoli, PhD, an assistant professor in the Institute for Systems Genetics at NYU Langone Health. "If we had a way to tell which patients would not respond, physicians could be quickly switching them to chemotherapies instead of exposing them to the considerable side effects that come with immunotherapy." Error-Prone Copying After initial genetic mistakes have transformed normal cells into cancer cells, other types of changes can make matters worse, the researchers say. Among these are changes in chromosome numbers, with some cancer cells containing more chromosomes than normal, and others less. Such copy number changes happen because errors occur as a cell divides into two and splits its chromosomes equally among its daughter cells, which occurs billions of times as a single-celled human embryo multiplies to form a fetus. At each division, copying errors can lead to the doubling, loss of, or shortening of chromosomes from one generation of cells to the next The likelihood of copying errors is much greater during the reckless growth driven by fast-dividing cancer cells, say the authors, which explains the "extensive" chromosome copy number changes present in most HPV-negative head and neck squamous-cell carcinomas. Head and neck cancers have many causes, and HPV-negative refers to those not caused by infection with the human papilloma virus (HPV). The much more common HPV-negative cancers are instead caused by smoking, alcohol use, and chromosome copy aberrations. A 2021 study led by the same research team had shown that the chromosome arm 9p is more likely to be lost in immune cold tumors that do not respond to immunotherapy. 9p houses many genes, including those that encode interferons, a set of immune system signaling proteins that can trigger attack on cancer cells, at a location (locus) called 9p21. The earlier study however, did not identify which region (and genes) on 9p were responsible for "immune cold" checkpoint therapy resistance. The new work suggests that the 9p24.1 locus, more than a 9p21 locus, may be the key. For the current analysis, the research team measured the extent of genomic loss of 9p24.1 in the cancer cells of patients with HNSC-HPVneg as captured by the National Cancer Institute's massive database on cancer cell genetics, the Cancer Genome Atlas, as well as in patient datasets from a company called Caris Life Sciences. The team linked 9p24.1 loss for the first time to survival duration after checkpoint inhibitor therapy. When the researchers next did a "whole exome" analyses of ten solid tumors, they also found that extra 9p24.1 led to immune cold features in patients with other squamous cancer types, including lung squamous cancers, cervical squamous cancer, and esophageal squamous cell carcinoma. 9p chromosome sections are known to include genes -- such as JAK2 -- Janus kinases (Jak) located on 9p24.1 -- that direct the production and response to interferons. In the team's hypothesis, extra copies or amounts of 9p24.1 increase the interferon response signaling in cancer cells through Jak signaling, which is known to recruit more NK cells and T cells to invade and attack tumor cells. "This finding justifies the development of 9p24.1 or Jak biomarker tests to select patients for checkpoint therapy," says first study author Xin Zhao, PhD, a post-doctoral Scholar in Davoli's lab. "Jak DNA or RNA expression may need to be incorporated into precision treatment strategies for any squamous or solid tumor in which 9p24.1 dosage shapes the environment near tumors." Funding for this research came from Instituto Cura; Cancer Research UK Grand Challenge, Mark Foundation for Cancer Research (C5470/A27144), the National Institutes of Health (grants R00 CA212621, R37 CA248631, R01DE026644, P01 CA106451, P50 CA097007 and P30 CA023100); an MRA Young Investigator Award; the Packard Fellowship for Science and Engineering; the National Foundation for Cancer Research; and Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Dream Team Translational Cancer Research (grant SU2C-AACR-DT-25-17).