In Japan, cervical cancer rates are on the rise, especially among younger women. Some breast and ovarian cancers are also known to develop from hereditary breast-ovarian cancer syndromes (HBOC), which are strongly associated with genetic factors. The treatment of cancer of the female reproductive organs, such as the uterus and ovaries, can have a profound impact on major events in a woman's life, from falling in love and getting married to pregnancy and childbirth. For this reason, it is necessary to not only provide treatment but also to confront serious questions about the probability of conception and whether a woman may have to abandon the idea of pregnancy altogether.
Prof. Daisuke Aoki of the Department of Obstetrics and Gynecology at the Keio University School of Medicine is an expert in gynecologic cancers. For many years, he has been tackling difficult issues associated with the treatment of cancer of the female reproductive organs and was one of the first to adopt medical treatments that consider both his patients and the small lives they may carry as mothers in the future. He continues to take a long-term approach to practicing gynecological medicine, developing guidelines for oocyte and sperm cryopreservation for patients with cancers and researching new cervical cancer screening methods.
In Japan, around 10,000 women develop cervical cancer, and close to 3,000 die from it each year. Cervical cancer has frequently been diagnosed in women in their 40s and 50s, but recently, its incidence has also increased among young women in their 30s and 40s, with both the number of patients and mortality rising since 2000.
Cervical cancer is caused by the human papillomavirus (HPV). It was in the 1980s that HPV was first found to cause cancer by infecting the cervix, located at the lower part of the uterus. However, one of the only tests approved for use on patients was cervical cytology, or the “PAP test,” in which a sample is collected from the cervix using a brush, then dyed to detect abnormal cells under a microscope.
“The HPV test is taken in the same way as a PAP test and detects HPV DNA in a specimen collected from the cervix to determine if the patient is infected with the virus,” Prof. Aoki says.
Some HPV infections can turn into cancer over a period of anywhere from five to ten years. In most cases, the body produces antibodies that clear the infection naturally, but if the infection persists, it can eventually lead to a precancerous state (precancerous lesion: squamous intraepithelial lesion [SIL], cervical intraepithelial neoplasia [CIN], dysplasia), with some infections eventually becoming cancerous. The HPV test, which directly determines the presence of the virus, can detect cancer and precancerous lesions as well as precancerous conditions caused by HPV infection, allowing doctors to nip cancer in the bud. The test also allows for the preservation of the uterus and can help in estimating the patient’s risk of developing cancer in the future.
Although HPV testing has been conducted in other countries, its effectiveness on Japanese individuals has remained unclear. To promote early-stage detection and reduce the number of cervical cancer cases, Prof. Aoki is leading a study to confirm the effectiveness of a new HPV test utilizing a cohort of 30,000 women who have undergone screening.
“Cervical cancer screening is done at two-year intervals, but HPV testing has the advantage of reducing that interval to once every five years,” Prof. Aoki explains, having conducted research with colleagues on the appropriate interval between screenings. In the 2020 update to the 2019 Japanese Guideline for Cervical Cancer Screening (National Cancer Center Japan), it was shown that the effectiveness of HPV testing is slightly higher than that of the conventional cytology screenings, but at the same time, the effectiveness of HPV testing may be inferior to cytology screenings if operating procedures and quality control measures are not put in place.
With many municipalities not yet equipped to handle the operating procedures and quality control measures required for cancer screenings, it is still too early to introduce these tests in Japan, and there are still plenty of issues that need to be addressed before they can be widely adopted across the country.
“For example, there is the issue of how to proceed with the diagnosis of people who test positive for HPV,” Prof. Aoki says. “Compared to smear tests, HPV testing has the advantage of higher sensitivity* but the disadvantage of lower specificity**, which means a higher number of false positives (people who test positive but are actually negative). With regular checkups, these false positives would number in the thousands, making the proper management of HPV positives rather difficult.”
*Sensitivity: The percentage of accurate positive results (abnormal values) when testing a group of people with a certain disease
**Specificity: The percentage of accurate negative results (normal values) when testing a group of people without a certain disease
Quality control measures and other management procedures are also critical to prevent cancer through cervical cancer screenings.
“The first step in conducting a medical check is to encourage the patient to undergo screening,” Prof. Aoki explains. “The trouble is that many women have a false sense of security once the first screening is over. But as doctors, we need to understand the whole process—from how many women have been tested to how many have needed further examination and if those who need further examination are receiving treatment. Yet some parts of the country have little grasp on this information.”
In Japan, cervical cancer screenings are conducted through local governments as a public health program to reduce cancer mortality. However, screening methods and frequencies are not standardized among local governments, and diagnostic procedures differ by region and medical institution. Therefore, Prof. Aoki is also conducting research to confirm whether this system is working properly. His findings will eventually be used to develop a consistent method of screening for use throughout Japan.
Many women believe that cervical cancer will eliminate their ability to become pregnant. So from their earliest studies, Prof. Aoki and his colleagues have researched and practiced methods to preserve the possibility of pregnancy for these women after treatment.
“The average age of mothers at childbirth is now approaching 30 or older, which coincides with the peak onset of cervical cancer. There is also a significant number of cervical cancer patients who have not yet had children but want to,” he says.
That is why, after confirming that pregnancy is possible, Prof. Aoki and his colleagues perform a radical trachelectomy for stage IB1 cervical cancer patients with lesions of 2 cm or less.
“This is a procedure in which the cervix is extensively removed, but the main body of the uterus is left intact, which allows the patient to become pregnant,” Prof. Aoki explains. “To date, we have performed this surgery on over 280 patients and have seen the birth of more than 100 babies thus far.”
In addition to surgery, hormone therapy is also used to preserve fertility in endometrial cancers that occur in the uterus where the fetus develops.
“Endometrial cancers are on the rise in all age groups,” Prof. Aoki explains. “And although the number is small, about 5% of all cancers occur in patients under the age of 40. In those cases, the conditions required to preserve fertility are limited, but hormone therapy can be used to eliminate the cancer if those conditions are met. To be eligible for this treatment, patients must meet strict criteria, such as their cancer being in an early stage and localized to the uterus. In 80–90% of these cases, the cancer disappears, and the patient can preserve fertility.”
To date, Prof. Aoki has provided hormone therapy to around 370 patients who have given birth to more than 100 babies. Although 70–80% of cancers treated by hormone therapy will eventually recur, for women and couples who strongly desire to have children, this treatment provides hope for the possibility of bringing new life into the world.
“In a sense, we use hormone therapy to buy time for the patient to become pregnant. But after surgery, we have both reproductive and perinatal specialists who follow up with patients, which is one of the strengths of our department,” Prof. Aoki says. “This also applies to the care we provide following cervical cancer surgery. About half of women can conceive naturally following a radical trachelectomy. However, even for those who are able to conceive, there is a higher risk of preterm delivery. I think it's rare to find a place like Keio where specialists in each field can work together to provide cancer patients with seamless care, from surgery to pregnancy and childbirth.”
Prof. Aoki also served as the chairperson of the Working Group on Guidelines for Fertility Preservation of Adolescent and Young Adult Patients with Cancers, which created rules for storing oocytes, or fertilized eggs, and sperm in order to preserve fertility in young patients with cancer.
“As a gynecologic oncologist, I can tell you that terms like ‘fertility preservation’ show that these cancers of the reproductive organs are different from other cancers. That is because, unlike other cancers, gynecologic cancers involve directly treating the reproductive organs. You can’t think of them in the same way as cases where germ cells (eggs and sperm) may be affected by chemotherapy or cases where the reproductive organs are directly removed,” Prof. Aoki explains, pointing out that getting pregnant in the future is not just a matter of saving eggs. “Because even if the eggs are preserved, it is impossible to conceive without the uterus. It's not just egg freezing that we need to consider if we want to preserve a woman’s chances of conception. Those are the types of issues that we have detailed in the guidelines.”
So what can doctors do to ensure future fertility for young patients that begin cancer treatment before the age of 40, including very young pediatric cancer patients? They can start by using the guidelines that Prof. Aoki and his colleagues have worked tirelessly to create, which more and more doctors across Japan are using to treat patients.
While the term “genomic medicine” has become increasingly common in recent years, gynecologic cancers have always been closely related to this emerging discipline. This is because some uterine and ovarian cancers are understood to be hereditary. For example, ovarian and breast cancers, known as hereditary breast-ovarian cancer syndromes (HBOC), are hereditary cancers caused by germline mutations (variants) in the genes BRCA1 or BRCA2. Hereditary ovarian cancers are often quickly growing serous cancers. BRCA1 or BRCA2 variants are passed down from parent to child with a 50% probability, regardless of gender. In families with a high incidence of breast or ovarian cancer, genetic testing can be used to identify the presence of pathological variants and take preventive strategies before they develop.
“Because people with pathological variants have a higher risk of cancer, it is recommended that they undergo risk-reducing salpingo-oophorectomy (RRSO; removal of both ovaries and fallopian tubes to help prevent ovarian cancer in healthy women) to reduce cancer mortality. RRSO is recommended because it has been shown to not only reduce the risk of developing cancer and improve ovarian cancer mortality but also to reduce all-cause mortality,” Prof. Aoki says. “In 2008, our department was the first in Japan to duly conduct an RRSO for ovarian cancer after approval by the university's ethics committee. In ovarian cancer cases, those with the BRCA1 variant normally develop cancer around the age of 35–40. In contrast, those with the BRCA2 variant are usually close to 50, so we have a window until then in which RRSO can be performed. Even those with the BRCA1 variant, which has a relatively early onset, can have children if they have them at a young age.”
With genomic medicine becoming more common, there will undoubtedly be more and more cases in which people undergo genetic testing only to find that they have a pathological variant. As one of the first to establish a system for providing preventive medical care to HBOC patients and their families, Prof. Aoki is concerned that, even if a variant is found, there are currently not many medical institutions that will be able to manage these patients.
In 2018, poly adenosine diphosphate-ribose polymerase (PARP) inhibitors were approved for treating ovarian cancer and have become something of a hot topic after showing excellent therapeutic effects. However, for new drugs like these to be approved for use, they must first go through careful clinical trials to verify their safety and effectiveness. Under Prof. Aoki's supervision, several clinical trials are being conducted simultaneously to confirm the therapeutic effects of combining these PARP inhibitors with other molecular targeted therapies (such as immune checkpoint inhibitors).
“Although many gynecologic cancers do not respond well to molecular targeted therapy, the recently introduced PARP inhibitors have demonstrated exceptional therapeutic effects and have improved the standard treatment of ovarian cancer. I am now working to build the evidence for combination therapy, combining PARP inhibitors with other drugs.”
Prof. Aoki also serves as the director of the Division of Clinical Research Support at the Keio University Hospital Clinical and Translational Research Center, which opened in 2014. Throughout his career, he has sowed the seeds of clinical research and fostered a new tradition in Keio’s Department of Obstetrics and Gynecology, which has a long history of basic research.
“When I first became a doctor, there was clinical training in obstetrics and gynecology, of course, but the focus was on basic research,” he says. “Keio was a bastion of basic research that had produced pioneers whose achievements include Japan's first cultured human cell and chromosome analysis. So lab culture at that time had a strong emphasis on that kind of basic medical science.”
Although the importance of basic research remains unchanged, Prof. Aoki started a new trend in clinical research when he began a large-scale clinical trial of a new drug just before taking up his professorship. He has since been involved in large-scale clinical trials involving multiple institutions in Japan and abroad. Through the process of engaging in numerous clinical studies and trials, he has helped cultivate a culture and tradition of excellence in the field of gynecologic oncology.
“When we joined an international collaborative multicenter study led by physician-scientists from several countries, it was a challenge to make sure that we met the different rules and regulations that apply in Japan and each researcher’s respective country. In recent years, more emphasis has been placed on clinical research, and I feel that it has become a much more integral part of our department,” explains Prof. Aoki, who helped bring about this clinical research sea change amongst the department’s long tradition of basic research.
He adds that “earnestness” is what he looks for in the next generation of medical students. “Because Keio is home to such cutting-edge medicine, it is critical to be earnest and diligent in understanding the high standard of care practiced here. And in order to ensure that these benefits reach as many patients as possible, I would like to come up with and research even better methods that will become new standards for treatment and offer new proposals for the future of medical checkups and other medical systems.” This logical thought process lies at the heart of Prof. Aoki's far-reaching work in both basic and clinical research.
1982 – Graduates from Keio University School of Medicine and starts residency at the Keio University Hospital
1988 – Works as a postdoctoral fellow at La Jolla Cancer Research Foundation (now Sanford-Burnham Medical Research Institute)
1989 – Earns a Ph.D. in Medicine
1990 – Serves as a doctor at the Second Tokyo National Hospital (now National Hospital Organization Tokyo Medical Center)
1991 – Serves as a research assistant at the Department of Obstetrics and Gynecology, Keio University School of Medicine
1996 – Serves as senior assistant professor of Obstetrics and Gynecology
2005 – Assumes current position as Medical Director of the Department of Obstetrics and Gynecology, Keio University School of Medicine