Recent Advances in Cervical Cancer Research

Cervical cancer has been getting much more attention as of late partly due to the HBO adaptation of Rebecca Skloot's book “The Immortal life of Henrietta Lacks.” As a survivor of the same type of cancer that took Henrietta’s life and led to the development of the HeLa cell line, Skloot's book resonated profoundly with me. Being diagnosed led me to learn more about cervical cancer, and after my experience, I felt compelled to increase awareness about this cancer, which is one of the most preventable cancers around.

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Cervical cancer is an abnormal and uncontrolled growth of the cells lining the cervix, which is somewhat like the doorway to the uterus. The cervix lining is mostly made up of one of two different cell types; lining the outer portion of the cervix facing the vagina are squamous cells, which are flat in shape. The open passage of the cervix which leads into the uterus is lined by glandular cells, which are more blocky in shape and produce mucus.  Cancer can arise from either of these cell types. Squamous cell cancers are the most frequent but adenocarcinomas, which develop from the glandular cells and are the most dangerous, have been increasing in incidence.

Unlike many other cancers, what causes the vast majority of cervical cancers is well known. Cervical cancer is unique in that it has a viral source, the Human Papilloma Virus (HPV). HPV is commonly known as the virus that causes genital warts, but what many don’t realize is that there are over a dozen types of sexually transmitted HPV, and only a few of them result in genital warts. What’s more worrisome are the HPV types are associated with cancers, with HPV 16 and 18 being the most common viruses for cervical cancer cases. The National Institutes of Health (NIH) highlight that persistent infection with certain HPV strains is the primary cause of most cervical cancer cases.

For many, an HPV infection carries a negative stigma, something only “promiscuous” people need to worry about. In truth, HPV infections are incredibly common in the United States, with 80-90% of sexually active men and women infected with at least one type of HPV throughout their lifetime.

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Because HPV has been found to cause cervical cancer, vaccines have been developed to prevent HPV infection in the first place, thus preventing cervical cancer. HPV vaccines are available to help reduce the risk of infection from HPV types 6, 9, 11, 16, 18, 31, 33, 45, 52, and 58 by stimulating the body to create antibodies against them. The HPV vaccines are virus-like particles, not actual viruses with viral DNA that can cause infections. However, for those who are already sexually active, these vaccines are not an option. Preventative measures do exist in the form of pap smears which are recommended for women between the ages of 21 - 65  (every 3 - 5 years). From my personal experience, I would go with 3. While cervical cancer is typically thought of as slow progressing cancer, some cases can progress very quickly, in as little as a year. Five year intervals can be too long for situations like this, and my own case a fast-developing cancer. Had I waited 5 years, I my chances of survival would have plummeted and the risk of more invasive cancer likely. If it is a possibility, why take the risk? Get tested as often as possible.

The standard of care for early-stage cervical cancer range from simply removing the lesion or a hysterectomy. But more problematic are later stage cancers which have spread to other organs, as they are more difficult to treat. Identifying effective treatments for later stage cancers has been progressing quickly as of late.

Recent Advances in Cervical Cancer Treatments

Immunotherapies have become a popular form of treatment in the cancer field. Many immunotherapeutic drugs are antibodies, which are proteins created by your immune system that can recognize and attack most things that create disease. Viruses, bacteria, even dust, and pollen can be attacked by antibodies, although one antibody protein can only recognize one target. Antibodies can now be created on a large scale and tailored to attack cancer-specific targets, which is what we call targeted immunotherapy.

Much of cancer treatment research goes into finding cancer-specific targets, sparing normal tissue. Effective targeted therapies have been developed, but they are limited to a few types of cancers; for example, an HER2-targeting antibody has been developed for many breast cancers. More recently, other targets with the potential to treat a broader scope of cancers have been discovered. One of these includes immune system checkpoint proteins. These proteins normally help the immune system recognize normal tissue, effectively telling immune cells to stand down. Cancer cells often use these same signals to hide from the immune system. With therapies targeting immune checkpoints, the immune system can be jump-started back up to fight against cancers. Many of these therapies are in clinical trials, with promising results, although much research remains to be done to identify side effects, since they work throughout the whole body, not just at the tumor. Other types of therapies include oncolytic viruses, which are believed to more easily infect and kill only cancer cells when compared to normal cells.

Chimeric antigen receptor T-cell (CART) therapy is another new immunotherapy. With CART therapy, immune cells are reprogrammed to attack cancer cells. T-cells are the main killer cells of the immune system and, like antibodies, each cell has a specific target it can recognize. Many cancers aren't recognized by these killer cells, so they aren't performing their job. T cells can be removed from a patient's blood and programmed to recognize and attack only cancer cells. These cells are multiplied and then infused back into the patient, where they go to work to attack cancer. Researchers are encouraged by the results of this treatment so far and it has moved to the clinical trial stage. Interleukin-2 (IL-2), a chemical made by immune cells to promote an immune response, is another treatment being studied to combat cancer. IL-2 causes T-cells to multiply, making them more effective. Each of these therapies has drawbacks, meaning that more research is required to refine the best techniques.

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Targeted therapies that do not depend on the immune system are also growing in popularity. These involve using drugs, rather than antibodies, to either stop the signals cancer uses to grow or tell the cancer to kill itself. Researchers are increasing their knowledge about the genetic changes that occur in tumor cells and using this information can develop drugs explicitly targeting genes that are very active in cancers but mostly inactive everywhere else. This approach limits drug side effects. Such therapies are usually used in combination with chemotherapy drugs, as some of them can also make traditional chemotherapies more effective.

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Some techniques help make current treatments more effective and efficient, such as Sentinel Lymph Node Biopsy (SNLB), a procedure used during surgery that incorporates a tracer, such as a blue dye. It is common practice to remove the lymph nodes in the in the pelvis to screen for metastasis of cervical cancer but through SNLB doctors can identify lymph nodes that contain cancer. When the tracer is injected into the area around the main tumor, the tracer will travel to the nearest lymph nodes, which is where metastatic cancer is also most likely to go. Lymph nodes containing the tracer can then be removed and screened for signs of cancer, letting doctors know whether the cancer has spread or not. Currently clinical trials are looking into combining SNLB with laparoscopically assisted surgery for less invasive procedures. Current research on this technique suggests SNLB is more effective in early-stage cervical cancers.

Targeting telomerase, a protein that helps prolong the life of dividing cells is a new strategy being studied to combat cancer. By removing the limitations cells usually have, telomerase allows cells to grow uncontrollably, leading to tumors.  Researchers have recently found an extract from the Inula viscosa plant that, by blocking telomerase, can inhibit uncontrollable cell growth in vitro. This is still far from being used in the clinic in humans, but it highlights the discoveries recent research has made towards treating cancer.

Disparities in Cervical Cancer Screening and Treatment

These recent developments in treating even metastatic cancer are encouraging, but when you look at how few women actually receive screening and treatment, one can’t help but feel distraught. A recent study found that cervical cancer death rates were significantly higher than had been previously reported in the United States, which is a shame since it is one of the most preventable cancers. This data is not new data but rather data that has been corrected by removing the portion of women who have undergone hysterectomies, making them unable to develop cervical cancer. Prior rates of mortality and death included women who have had hysterectomies and thus no cervix, deflating the number of at-risk women.

 Trends in age-standardized cervical cancer mortality rates, uncorrected and corrected for the prevalence of hysterectomy, from 2000 to 2012. Source: Beavis, A. L., Gravitt, P. E. and Rositch, A. F. (2017), Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer, 123: 1044–1050. doi:10.1002/cncr.30507

Trends in age-standardized cervical cancer mortality rates, uncorrected and corrected for the prevalence of hysterectomy, from 2000 to 2012. Source: Beavis, A. L., Gravitt, P. E. and Rositch, A. F. (2017), Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer, 123: 1044–1050. doi:10.1002/cncr.30507

However, this study is still not a complete picture of the true disparity in incidence and mortality rates of cervical cancer between women of color and white women, since it excludes other significant minority populations, such as Hispanic/Latina women. The NIH National Cancer Institute (NCI) website's statistics for 2000-2004 show that Hispanic/Latina women have the highest incidence of cervical cancer, whereas African American/Black women have the highest death rates. This disparity is due to lack of screening in these populations which is correlated to unequal access to health care.There is a significant association between lower socioeconomic status and incidence/mortality. The easier it is to access healthcare, the more frequent screening will be and the likelihood of diagnosing cervical cancer at an early stage is increased.

“Nowhere is this failure of our health care system more apparent than in the disparities in cervical cancer incidence and outcome… suffered by members of particular racial and ethnic minority subgroups and other underserved populations... Cervical cancer (is) a disease for which effective prevention—not just early detection—and treatment have existed for decades.” -Harold P. Freeman, M.D. National Cancer Institute, Center to Reduce Cancer Health Disparities (immediate past director)

Incidence and death rates in Texas alone are twice as high according to the NIH. Only half of the Texan population has health insurance and many of those that do still can't afford routine screenings because their deductibles are too high. The South, in general, has an increased mortality rate compared to the national average. A recent study outlined the age-specific differences seen in incidence and mortality between non-Hispanic whites (NHW) and non-Hispanic blacks (NHB), showing that NHB women have a significant increase in both incidence and mortality at all ages.

 Age-specific cervical cancer incidence and mortality rates in the South by race (2008–2012). Source: Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States Wonsuk Yoo Sangmi Kim Warner K. Huh Sarah Dilley Steven S. Coughlin Edward E. Partridge Yunmi Chung Vivian Dicks Jae-Kwan Lee Sejong Bae[/caption]

Age-specific cervical cancer incidence and mortality rates in the South by race (2008–2012). Source: Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States
Wonsuk Yoo Sangmi Kim Warner K. Huh Sarah Dilley Steven S. Coughlin Edward E. Partridge Yunmi Chung Vivian Dicks Jae-Kwan Lee Sejong Bae[/caption]

Given this data, increasing/expanding affordable access to screening services would help address this disparity, but these initiatives must be targeted to at-risk populations, and practitioners need to be made aware of these issues in the populations they serve to help tackle the problem.

Follow the links below for more information on Cervical Cancer.

Find out more about ways to reduce cervical cancer mortality in vulnerable populations

NIH/NCI Division of Cancer Control & Population Sciences

NIH/NCI Spanish Website

Cervical Cancer Health Disparities Fact Sheet

HPV Vaccine Information

Sources:

Beavis, A. L., Gravitt, P. E. and Rositch, A. F. (2017), Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer, 123: 1044–1050. doi: 10.1002/cncr.30507:

Yoo W, Kim S, Huh WK, Dilley S, Coughlin SS, Partridge EE, et al. (2017) Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States. PLoS ONE 12(2): e0172548. https://doi.org/10.1371/journal.pone.0172548

Merghoub, N., El Btaouri, H., Benbacer, L., Gmouh, S., Trentesaux, C., Brassart, B., Attaleb, M., Madoulet, C., Wenner, T., Amzazi, S., Morjani, H. and El Mzibri, M. (2017), Tomentosin Induces Telomere Shortening and Caspase-Dependant Apoptosis in Cervical Cancer Cells. J. Cell. Biochem., 118: 1689–1698. doi:10.1002/jcb.25826

American Cancer Society. Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society; 2016.

Singh et al., Persistent Area Socioeconomic disparities in U.S. incidence of cervical cancer, mortality, stage and survival,1975 - 2000:

Houston Chronicle. Mike Hixenbaugh. Houston doctors determined to reduce cervical cancer deaths in Rio Grande Valley, November 25, .2016