Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington

Dr. Brewer reports no financial relationships relevant to this field of study.

SYNOPSIS: Genetic testing is changing rapidly. With the advent of more sophisticated genetic mutation panels, it is important that providers of women’s healthcare consider appropriate referral and testing for those women at increased risk of malignancy.

SOURCE: Ring KL, Garcia C, Thomas MH, Modesitt SC. Current and future role of genetic screening in gynecologic malignancies. Am J Obstet Gynecol 2017;217:512-521.

With the advent of new panels screening for genetic oncologic mutations and as first-line clinicians for women, gynecologists need to be aware of the changes that have occurred over the last two years in genetic testing. As outlined by Ring et al, the current recommendation is panel testing for women with a strong family history of gynecologic cancers, such as ovarian or endometrial cancer, and a personal history of breast, ovarian, or endometrial cancer. Since Myriad Genetics lost its patent on the BRCA genes,¹ many companies now offer genetic panels that test for a number of genes that only recently have been associated with gynecologic and breast cancers. Even five years ago, ovarian cancer was thought to be associated only with a deleterious germline mutation 5-10% of the time. As these authors note, approximately 24% of ovarian cancers are associated with a germline mutation.² Unfortunately, there still is not consistent identification of women at risk for germline mutations nor consistent referral for testing for these mutations.³

Although BRCA1 and BRCA2 are the more commonly recognized gene mutations, multiple other pathways may carry germline mutations leading to gynecologic cancers. One pathway leads to acquisition of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). Lynch syndrome is responsible for approximately 15% of hereditary ovarian cancers, which often histologically are endometrioid or clear cell cancers. These women are at increased risk of colorectal, endometrial, gastric, small bowel, genitourinary, pancreatic, and glioblastoma cancers. Approximately 8% of all endometrial cancers are associated with Lynch syndrome.

In addition to BRCA1 and BRCA2 mutations, other mutations of DNA repair pathways affect RAD51C, RAD51D, and BRIP1, which may carry a 10% lifetime risk of ovarian cancer.⁴ PALB2 and BARD1 are associated with an increased risk of breast cancer, but have not been associated with ovarian cancer.

Another identifiable oncologic gene mutation is the one associated with PTEN (Cowden syndrome). Women with these mutations have up to a 28% risk of endometrial cancer as well as hamartomas, which usually are benign lesions. POLD1, which works with the Lynch syndrome genes, has an increased risk of both endometrial and colon cancer.⁵ Women with a BRCA1 mutation have an increased risk of serous endometrial cancer.⁶ Women with adenoma malignum of the cervix may have Peutz-Jeghers syndrome, and young women with rhabdomyosarcoma may carry a DICER1 mutation. These women should be considered for genetic testing. These are all examples of gynecologic cancers associated with identifiable gene mutations.

COMMENTARY

So how can women’s health providers keep these new germline mutations straight? The most important aspect of patient care in a suspected patient is to take a careful family history and make appropriate referrals to one of several practitioners, depending on the individual’s needs.⁷ If you have access to a cancer genetic counselor, it is more appropriate to refer patients for genetic counseling and appropriate testing, because genetic counselors are more up-to-date on what to test for as well as how to counsel patients.

Barriers to genetic testing are mainly due to the lack of consistent information on the importance of genetic testing.⁸ If you do not have access to genetic counselors, panel testing is a reasonable alternative. However, prior to making treatment recommendations, it would be prudent to seek help about how to counsel patients on interpretation of the test results. A surgical oncologist can better counsel on appropriate breast cancer strategies and a gynecologic oncologist can better counsel on appropriate gynecologic strategies. Removing a woman’s ovaries and tubes before she has children probably is not in the patient’s best interest, even if her gene panel is positive. This requires delicate counseling and screening recommendations. However, increased screening may be appropriate for both breast and ovarian cancer, depending on the mutation discovered.

One of the errors I see routinely is the referral of a patient with a mutation that is considered a variant of uncertain significance for prophylactic surgery. It is not appropriate to recommend prophylactic surgery unless the variant is reclassified as a deleterious mutation. Again, this is better managed with the help of genetic counselors who routinely communicate with the companies that follow these mutations and reclassify those mutations as deleterious if they track with clusterings of cancer. If they are reclassified as benign polymorphisms, then the patient not only does not need prophylactic surgery, she does not need increased surveillance.

The world of cancer-associated mutations has changed dramatically in the last 10 years and we expect it to continue to do so. To keep up with new findings, it is important to have a relationship with a genetic counselor and a gynecologic oncologist who can help sort through these new changes.

REFERENCES

1. Servick K. End of the road for Myriad gene patent fight. Science Available at: http://www.sciencemag.org/news/2015/01/end-road-myriad-gene-patent-fight. Accessed Feb. 23, 2018.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
3. Hoskins PJ, Gotlieb WH. Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature. CA Cancer J Clin 2017;67:493-506.
4. Ramus SJ, Song H, Dicks E, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst 2015;107:djv214.
5. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013;45:136-144.
6. Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol 2016;2:1434-1440.
7. Committee on Gynecologic Practice, Society of Gynecologic Oncology. Committee Opinion No. 716: The role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer in women at average risk. Obstet Gynecol 2017;130:e146-e149.
8. Shaw J, Bulsara C, Cohen PA, et al. Investigating barriers to genetic counseling and germline mutation testing in women with suspected hereditary breast and ovarian cancer syndrome and Lynch syndrome. Patient Educ Couns 2017; Dec. 12. pii: S0738-3991(17)30657-2. doi: 10.1016/j.pec.2017.12.011. [Epub ahead of print].