In 2016, a growing understanding of cancer biology has spurred new insights into genetic mutations that predispose people to different cancers. Knowing that a person carries a mutation in a cancer susceptibility gene is important, because outcomes can be improved through frequent cancer screening and preventive surgery. In addition, identifying cancer susceptibility factors can help direct cancer treatment decisions and inform family planning.
Every opportunity to prevent cancer is welcome news. Last year, researchers reported on a new way to reduce the risk of nonmelanoma skin cancer: a simple vitamin B pill. In addition, ASCO issued a policy statement outlining recommendations to increase the uptake of human papilloma virus (HPV) vaccination. These vaccines prevent cervical and other HPV-related cancers and have the potential to save millions of lives. Meanwhile, researchers identified a range of barriers that contribute to lower cervical and breast cancer screening rates among Latina women.
Additional Genes Linked to Ovarian Cancer Risk
A woman with a single first-degree relative (e.g., mother, daughter, or sister) with ovarian cancer has a three-fold increased risk of developing ovarian cancer; the risk goes up when two or more first-degree relatives have been diagnosed with ovarian cancer. More information on ovarian cancer and familial risk can be found at Cancer.Net.
An estimated 10% to 15% of ovarian cancers are linked to genetic mutations that are passed down within a family. For example, the chance of developing ovarian cancer is 36% for women with mutations in the BRCA1 gene and 12% for those with mutations in BRCA2. By comparison, in the general population of women, the risk of developing ovarian cancer over a lifetime is only 1% or 2%.36
A recent large study showed that mutations in two other genes may make women susceptible to ovarian cancer. Women with mutations in RAD51C and RAD51D genes have a five- and twelve-fold higher risk for ovarian cancer, respectively, than women in the general population (this study was funded in part by a grant from the NIH).37 In fact, researchers estimate that mutations in RAD51 genes may be responsible for one in every 120 ovarian cancers.
Although these mutations are rare, knowing that a woman has these risk factors is important, because steps can be taken to lower ovarian cancer risk. The findings from this study have led to a change in the national guidelines on genetic testing. The updated guidelines recommend consideration of surgery (salpingo-oophorectmy) to reduce the risk of ovarian cancer in women who have mutations in RAD51C or RAD51D genes. For women with high-risk gene mutations, such as BRCA1 and BRCA2, the genes related to Lynch syndrome, and others, having the ovaries and fallopian tubes surgically removed can reduce ovarian cancer risk by 70% to 96%.
For women who are already diagnosed with ovarian cancer, testing for RAD51 gene mutations can also inform treatment decisions. Past research has suggested that women who have such mutations may respond well to a novel class of drugs known as poly (ADP-ribose) polymerase (PARP) inhibitors.
A Policy Focus: Genetic Testing
Genetic counseling and testing has become a growing part of cancer risk assessment, diagnosis, and treatment planning. Through policy statements, expert guidelines, and quality programs, ASCO is helping oncology professionals integrate genetic counseling and testing into clinical practice.
In the context of cancer, genetic testing can be used to confirm or rule out a hereditary predisposition to cancer (approximately 5% to 10% of cancers are hereditary) and to identify genetic changes in cancer cells that may respond to specific molecularly targeted cancer treatments, helping a physician and patient identify the best treatment option.
During the past year, some insurance companies have adopted policies that hinder oncologists’ ability to order genetic tests for their patients. ASCO opposes any policy that introduces an unnecessary barrier to the appropriate use of genetic testing services or has the potential to negatively affect patient care.
Pancreatic Cancer Susceptibility Genes identified, and New Opportunities for Screening and Prevention
Approximately one in 10 pancreatic cancers is associated with a gene mutation that is passed on in a family from one generation to the next. When pancreatic cancer occurs in two or more first-degree relatives, it is referred to as familial pancreatic cancer. Predisposition to pancreatic cancer has been linked to mutations in a number of different genes, including BRCA1 and BRCA2. In 2015, a prospective study found BRCA mutations in 5% of patients with the most common type of pancreatic cancer: pancreatic ductal adenocarcinoma.38
However, the frequency of BRCA mutations was higher (12%) among 33 patients of Ashkenazi Jewish descent. (According to prior studies, BRCA mutations are also more common among Ashkenazi women with breast or ovarian cancer, compared with the general population). Although the numbers were small, this finding led to a change in national genetic testing guidelines so that every Jewish individual with pancreatic cancer is recommended to undergo BRCA1/2 testing. Relatives of BRCA1/2 mutation carriers who are found to have the familial mutation can be offered appropriate preventive strategies, including screening to detect pancreatic cancer at an early stage.
Given that the average person has only a 1% chance of developing pancreatic cancer over a lifetime, general screening for pancreatic cancer is not recommended. However, selective screening of people who are at high risk for pancreatic cancer may detect premalignant tumors or early-stage cancers, both of which are potentially curable with surgery.
The benefit of such screening was evaluated in a recent prospective screening study of 411 asymptomatic people with familial pancreatic cancer or mutations in known pancreatic cancer susceptibility genes (e.g., CDKN2A, BRCA1/2, and PALB2).39 Screening tools included annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and endoscopic ultrasound. The median follow-up time was 32 months.
Pancreatic ductal adenocarcinoma was detected in 13 (7%) of 178 CDKN2A mutation carriers, nine of whom underwent surgery. The 5-year survival rate was 24%, which is five-fold higher than the 5-year survival rate for all patients diagnosed with this cancer. In addition, screening detected pancreatic cancer in only two (0.9%) of 214 individuals with familial pancreatic cancer and one (5%) of 19 patients with BRCA mutations.
This study is the first to our knowledge to demonstrate success in detecting early cancers and favorable outcomes with surgery using pancreatic cancer screening in a high-risk population. Although screening was clearly useful in detecting pancreatic cancer among patients with CDKN2A mutations, more research is needed to assess the benefit of screening in other high-risk groups, such as people with familial pancreatic cancer or BRCA mutations.
Voices of Cancer Research: David Dessert
In 2010, a pancreatic cancer diagnosis confirmed it: David carried a BRCA2 gene mutation that increased his risk of certain cancers. The treatment David received at the time was successful, but the risk of his cancer returning was high. A clinical trial, however, gave him new hope. For the past three and a half years, David has been receiving the GVAX vaccine, an immunotherapy designed to reduce the risk of pancreatic cancer recurrence.
“Every treatment we have right now, we have because someone else tried it in a clinical trial,” David said. “Hopefully this will help somebody else down the line.”
David is a pancreatic cancer forum moderator at cancerforums.net, a member of the peer navigator program at Facing Our Risk of Cancer Empowered (FORCE), and a blogger for pancreatica.org.
Broader Testing Uncovers Unexpected Cancer Predisposition Gene Mutations
People with Lynch syndrome have a markedly increased risk of developing colorectal, endometrial, ovarian, gastric, pancreatic, urinary tract, and other cancers, often at a young age. The syndrome is caused by mutations in the following genes: MLH1, MSH2, MSH6, PMS2, or EPCAM. Conventional Lynch syndrome testing only screens for mutations in these five genes. However, up to half of families with suspected Lynch syndrome test negative for such mutations, which suggests that other genetic changes may be causing increased risk of cancer.
To address this question, researchers used a new technology known as multigene panel testing, which can rapidly analyze numerous cancer susceptibility genes (this study was funded by a grant from the NCI).40 They evaluated 25 cancer predisposition genes among 1,260 people who were referred for Lynch syndrome testing.
Although 114 (9%) participants had a mutation in one of the Lynch syndrome genes, 71 (6%) had mutations in other cancer predisposition genes. For example, 15 people had mutations in BRCA1 or BRCA2 genes (linked to increased chance of developing breast, ovarian, and other cancers), and nine other individuals had a mutation in a colorectal cancer susceptibility gene.
This study shows that multigene panel testing may yield clinically useful information that could be missed by the more limited, traditional Lynch syndrome testing. It could reveal genetic changes that would not be suspected based on family history alone, allowing for preventive measures such as screening and surgery.
One downside of broad-based genetic testing, however, is the possibility of discovering genetic mutations that have an uncertain clinical significance. Such findings can cause considerable anxiety in patients. In this study, 38% of the people tested had one or more such uninformative findings.
Many Children With Cancer May Carry Hereditary Gene Mutations
The reasons a child develops cancer are often poorly understood. It is largely unknown how common hereditary mutations in cancer predisposition genes arise in children with cancer. A better understanding of the genetic basis for childhood cancer susceptibility would inform treatment choices as well as genetic counseling for patients’ families.
To address this gap in knowledge, researchers conducted a large-scale genomic study of children diagnosed with cancer before the age of 20 years (this study was funded in part by a grant from the NCI).41 The analysis focused on 565 genes, including 60 that have previously been associated with cancer predisposition syndromes.
They detected mutations in genes thought to be linked to increased cancer risk in 8.5% of 1,120 children with cancer, a rate that was much higher than that observed in a control group of 1,000 people without cancer (1.1%). Interestingly, the majority (60%) of children with a hereditary cancer predisposition mutation did not have a family history of cancer.
These findings argue for greater screening for hereditary genetic predisposition in children with cancer, even in the absence of a family history of cancer. For the patient, identification of hereditary mutations may influence treatment selection and guide family planning. For the patient’s relatives, having this information can prompt them to request their own genetic testing and/or consider cancer prevention measures.
A Policy Focus: ASCO Calls for Increased Use of HPV Vaccination to Prevent Cervical Cancer
In April 2016, ASCO released a policy statement calling on its member oncologists to help lead the push for all adolescents and young adults to be vaccinated against cervical and other cancers. Published in the Journal of Clinical Oncology, the statement outlines current barriers to the use of HPV vaccination, and recommendations to promote the uptake of these vaccines, which have the potential to save millions of lives.
ASCO supports the recommendation to markedly increase the proportion of young boys and girls receiving the HPV vaccine in the United States and worldwide because research has shown that it is effective in preventing cancer. Ongoing research confirms the public health benefit of HPV vaccines for preventing cervical cancer.1
To this end, ASCO believes oncologists can play a vital role in increasing the uptake of HPV vaccines. Although most oncologists are not the direct health care providers for these preventive measures, they play an important role through research and advocacy. ASCO encourages oncologists to advocate for and actively promote policy changes to increase the use of HPV vaccination.
1 Bernard VB, Castle PE, Jenison SA, et al.: Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol [epub ahead of print on September 29, 2016]
Daily Vitamin B Reduces Skin Cancer Risk
Excessive sun exposure is a widely recognized risk factor for skin cancer. Despite sun protection campaigns, the rates of skin cancer continue to rise worldwide. Nonmelanoma skin cancer is the most common type of cancer in fair-skinned populations worldwide. More than one in two Australians will develop a nonmelanoma skin cancer in their lifetime.42 In the United States, 5 million people are treated for skin cancer every year.43 Although nonmelanoma skin cancer is rarely fatal, its treatment poses a significant burden on health care systems.
Over the past decades, researchers have explored a broad range of vitamins and supplements for cancer prevention. However, only a few substances with properties protective against cancer have been identified to date. Recent research identified a form of vitamin B3 called nicotinamide that can lower the chance of developing skin cancer in people who are at high risk for the disease.
In a clinical trial of people with a history of nonmelanoma skin cancers, the rate of new skin cancer diagnoses was 23% lower among people who took the vitamin twice a day for a year.44 This is the first clear evidence that skin cancers can be prevented using a simple, inexpensive vitamin, along with sun protection. Nonetheless, people at high risk for skin cancer should continue to have regular check-ups with their physicians.
This clinical trial builds on a decade of preclinical and early clinical studies suggesting that nicotinamide not only helps skin cells repair DNA damaged by UV radiation but also protects the skin’s immune system against UV light. The skin’s immune system helps eradicate abnormal cells before they become cancerous.
New Understanding of Barriers to Cancer Screening Among Latinas
In the United States, Latina women have the lowest rates of compliance with cervical and breast cancer screening recommendations. Women who have long gaps between screenings or do not receive any screening face a lower chance of successful treatment and consequently shorter survival.
Although prior research has explored extrinsic sources of disparity in screening adherence, such as limited access to care and lack of health insurance, relatively little is known about intrinsic factors, such as perceptions and attitudes. A survey of 87 Latina women from New York and Arkansas who were enrolled in a culturally tailored education program to increase breast and cervical cancer screening adherence has provided a wealth of information on a variety of factors.45
Despite completing the education program, the women were noncompliant with at least one of the recommended screening examinations (clinical breast examination or mammogram for breast cancer; Pap test for cervical cancer). The most commonly reported reasons for noncompliance were logistic and organizational barriers (e.g., being out of the country for long periods of time, forgetting to schedule an appointment), lack of time (e.g., inability to take time off from work), and lack of interest in having a screening test. In addition, several women were confused about when they were due for an examination, and others believed they did not need an examination as often as guidelines recommend.
These new insights into factors that contribute to perceptions of cancer screening may enable development of tailored programs to improve screening rates. Similar methodology can be used to direct interventional programs related to other aspects of cancer care.
For additional notable advances in cancer prevention and screening, please see Appendix Table A1.