Genetics and ovarian cancer

Genetics and Ovarian Cancer

Hereditary risk and genetic mutations in ovarian cancer

Advances in genetic research are rapidly changing our understanding of ovarian cancer1

As with other cancers, ovarian cancer develops as a result of mutations in certain genes, such as those involved in the regulation of cell growth or DNA repair. These gene mutations can be hereditary (germline) or sporadic / non-hereditary (somatic).2

In individuals with hereditary cancer, a mutation in a tumor suppressor gene can be inherited from either parent and result in one mutated copy and one wild-type copy of the gene in every cell of their body. These individuals require only one additional mutation to knock out the remaining functional copy of the gene, thus increasing their susceptibility to the development of cancer.2

Genetic mutations in hereditary vs. non-hereditary ovarian cancer

There are several genes associated with ovarian cancer, the most common of which are BRCA1 and BRCA21,2

Several genes have been discovered that contribute to inherited susceptibility for developing ovarian cancer, such as BRCA1, BRCA2, PTEN, TP53, CDH1, CHECK2, PALB2, BRIP1, RAD51C, among others.2

Germline BRCA-mutated ovarian cancer accounts for a large percentage of known hereditary ovarian cancers.3 In addition, a higher proportion of women diagnosed with high-grade serous ovarian cancer have a BRCA1/2 mutation compared with other subtypes.4,5

BRCA1 and BRCA2 are the most common genes associated with ovarian cancer

Mutations in the BRCA1/2 genes have a relatively high rate of penetrance, estimated at an 11% to 62% lifetime risk for developing ovarian cancer, depending on the population studied.2 Penetrance can be incomplete and may appear to skip generations, but both males and females can pass on and inherit a BRCA1/2 mutation.6

Development of Hereditary Cancer 2

BRCA mutations can be attributed to founder mutations among specific populations, notably women of Ashkenazi Jewish heritage, with other populations found in the Netherlands, Sweden, Hungary, Iceland, and among French-speaking areas of Canada.2 However, in general, hereditary mutations are relatively evenly distributed across ethnicities.7

BRCA1/2 and other gene mutations have been linked to secondary cancers in patients with ovarian cancer8

BRCA1/2 mutations lead to deficiency in the repair of DNA double-strand breaks. The resulting genomic instability creates an increased risk of secondary forms of cancer, namely breast, colon, and in men, prostate—a risk that increases over time.8,9

Age-Specific Cancer Risks9:

REFERENCES

1. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278(5340):1043–1105. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2015. 3. Ferla R, Calò V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18(suppl 6):vi93-vi98. 4. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180. 5. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473-2481. 6. National Cancer Institute. BRCA1 and BRCA2: Cancer risk and genetic testing. Fact sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA. 7. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 8. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 9. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series selected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 10. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 11. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. 12. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 13. Eichmeyer JN, Burnham C, Sproat P, Tivis R, Beck TM. The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. J Genet Couns. 2014;23(3):323-329. 14. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 15. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 16. King MC, Marks JH, Mandell JB; The New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):642-646. 17. Ford J. BRCA1 and BRCA2: Clinical genomics and target for therapeutics. Presented at: 2014 ASCO Annual Meeting, June 1, 2014. Chicago, IL. 18. Geier L. BRCA mutation carriers: how to find them, what to do with them. Presented at: 2013 Community Oncology Alliance Conference; March 20-23, 2013. 19. FORCE Web site. Understanding BRCA & HBOC > Finding Specialists & Paying for Care > Insurance & Financial Issues; http://www.facingourrisk.org. Accessed November 17, 2014. 20. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 21. Tan DSP, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530-5536. 22. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260-2265. 23. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 24. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. 25. Genetic Information Non-Discrimination Act, 42 USC § 2000ff-10 (2008).

Ovarian Cancer Guidelines and Society Statements

Guidelines and Society Statements

Recommendations and rationale from leading oncology organizations

Leading oncology organizations recommend that all patients with epithelial ovarian cancer be considered for BRCA testing

Excerpts from the NCCN Guidelines Version 2.20152*

Excerpts from the NCCN Guidelines Version 2.2015: Hereditary Breast and/or Ovarian Cancer Syndrome

HEREDITARY BREAST AND/OR OVARIAN CANCER SYNDROME TESTING CRITERIA

  • Personal history of invasive ovarian cancer

"[T]he NCCN Panel recommends testing for patients with a personal history of invasive ovarian cancer...diagnosed at any age."

—page MS-9

View the full NCCN Guidelines

Excerpts from the American Society of Clinical Oncology Expert Statement10

Excerpts from the American Society of Clinical Oncology Expert Statement

Cancers for Which Genetic Counseling and Testing Should Be Considered, Even in Absence of Family History:

  • Epithelial ovarian, fallopian tube, or primary peritoneal cancer (most commonly, high-grade serous histology)
View the full ASCO Statement

Excerpts from the SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer October 201411

Excerpts from the SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer October 2014

Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of a family history.

Therefore, all women diagnosed with ovarian, fallopian tube or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing.

The Society of Gynecologic Oncology (SGO) encourages the medical community to offer genetic counseling and testing to all women with ovarian, fallopian tube and peritoneal carcinoma.

View the full SGO Statement

Rates of BRCA testing fall well below recommended guidelines12

A number of studies have shown that between one-third and three-quarters of patients who have cancer and are referred for genetic counseling either do not follow through with the appointment or are not tested because of appointment coordination difficulties, financial concerns, a perceived lack of benefit, or other reasons.13

REFERENCES

1. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278(5340):1043–1105. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2015. 3. Ferla R, Calò V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18(suppl 6):vi93-vi98. 4. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180. 5. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473-2481. 6. National Cancer Institute. BRCA1 and BRCA2: Cancer risk and genetic testing. Fact sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA. 7. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 8. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 9. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series selected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 10. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 11. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. 12. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 13. Eichmeyer JN, Burnham C, Sproat P, Tivis R, Beck TM. The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. J Genet Couns. 2014;23(3):323-329. 14. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 15. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 16. King MC, Marks JH, Mandell JB; The New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):642-646. 17. Ford J. BRCA1 and BRCA2: Clinical genomics and target for therapeutics. Presented at: 2014 ASCO Annual Meeting, June 1, 2014. Chicago, IL. 18. Geier L. BRCA mutation carriers: how to find them, what to do with them. Presented at: 2013 Community Oncology Alliance Conference; March 20-23, 2013. 19. FORCE Web site. Understanding BRCA & HBOC > Finding Specialists & Paying for Care > Insurance & Financial Issues; http://www.facingourrisk.org. Accessed November 17, 2014. 20. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 21. Tan DSP, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530-5536. 22. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260-2265. 23. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 24. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. 25. Genetic Information Non-Discrimination Act, 42 USC § 2000ff-10 (2008).

Myths and facts of BRCA testing

Myths & Facts of BRCA Testing

Why screening based on family history, age, or ethnicity can miss patients with a BRCA mutation

Screening based on family history or age misses a substantial number of ovarian cancer patients who have a BRCA1/2 mutation8,14

It is commonly thought that traditional predictive indicators of BRCA-mutated ovarian cancer, such as a patient's family history or age at diagnosis, can be used to identify patients for testing for a BRCA1/2 mutation. However, evidence shows that testing only those with a family history of breast or ovarian cancer or only those diagnosed at a young age misses up to half of all patients with a BRCA mutation.

Of Women with BRCA-Mutated Ovarian Cancer

Myths and facts about BRCA testing and ovarian cancer

MYTH

BRCA status does not affect clinical decisions and outcomes.

FACT

BRCA status can be predictive of response to therapies2,4

MYTH

If a patient with ovarian cancer has no family history of breast or ovarian cancer, they should not be tested for a BRCA1/2 mutation.

FACT

National guidelines and society statements recommend epithelial ovarian cancer patients be considered for BRCA testing even if they do not have a family history of breast or ovarian cancer. Family history may not be a reliable indicator of the presence of a deleterious BRCA1/2 mutation. In fact, up to 47% of all women with ovarian cancer and a BRCA mutation have no history of cancer in their families.2,4,10,11,15

  • Patients may come from a low-incidence family, in which none of the direct female relatives—mothers, sisters, grandmothers, or aunts—has breast or ovarian cancer2,16
  • Absence of cancer in the patient’s immediate family may be a result of an inherited mutation on the paternal side of the family, explaining why cancer instances may appear to "skip" generations16,17
  • Family members inherit an altered cancer susceptibility gene, not cancer itself, so the cancer may never materialize, despite risk17
  • Patients may lack an adequate family history for variety of reasons, including:
    • misinterpreted cancers as other conditions
    • early death of family members from other causes
    • unavailability of records and/or lack of awareness of family history10,18
Support

MYTH

Because patients with BRCA1/2 -mutated ovarian cancer are diagnosed at a younger age, BRCA testing is less relevant for patients 50 years or older.

FACT

71% of patients with ovarian cancer who have a BRCA1/2 mutation are 50 years or older when they were diagnosed, and 32% are older than 60.15

  • When a patient is diagnosed with cancer at an uncharacteristically young age, a genetic component may be present. However, ovarian cancer often presents later regardless of the presence of a BRCA1/2 mutation or other inherited risk2
Support

MYTH

BRCA testing is not covered by insurance and is too expensive for my patients.

FACT

Patients have very good access to testing. Almost all insurance plans cover BRCA testing, and most patients incur no out-of-pocket costs.19 There is also assistance available for low-income patients who are underinsured or uninsured.19

MYTH

Only a very small percentage of ovarian cancers are associated with BRCA mutations

FACT

As many as 1 in 7, or 14%, of ovarian cancers are associated with a BRCA mutation.20

REFERENCES

1. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278(5340):1043–1105. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2015. 3. Ferla R, Calò V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18(suppl 6):vi93-vi98. 4. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180. 5. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473-2481. 6. National Cancer Institute. BRCA1 and BRCA2: Cancer risk and genetic testing. Fact sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA. 7. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 8. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 9. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series selected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 10. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 11. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. 12. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 13. Eichmeyer JN, Burnham C, Sproat P, Tivis R, Beck TM. The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. J Genet Couns. 2014;23(3):323-329. 14. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 15. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 16. King MC, Marks JH, Mandell JB; The New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):642-646. 17. Ford J. BRCA1 and BRCA2: Clinical genomics and target for therapeutics. Presented at: 2014 ASCO Annual Meeting, June 1, 2014. Chicago, IL. 18. Geier L. BRCA mutation carriers: how to find them, what to do with them. Presented at: 2013 Community Oncology Alliance Conference; March 20-23, 2013. 19. FORCE Web site. Understanding BRCA & HBOC > Finding Specialists & Paying for Care > Insurance & Financial Issues; http://www.facingourrisk.org. Accessed November 17, 2014. 20. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 21. Tan DSP, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530-5536. 22. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260-2265. 23. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 24. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. 25. Genetic Information Non-Discrimination Act, 42 USC § 2000ff-10 (2008).

Testing for BRCA1/2 mutation in patients diagnosed with ovarian cancer

Clinical Implications of BRCA Testing

How knowing your patient's BRCA status can help personalize care

BRCA status can inform disease management throughout the ovarian cancer care continuum

  • Diagnosis
  • Debulking
    surgery
  • Front-line therapy
  • Surveillance
    +/- maintenance
  • Recurrent
    therapy

Prognosis

Recurrence-Free Interval Probabilities in Patients With Advanced-Stage (III and IV) BRCA-Associated (n=81) and Sporadic (n=100) Ovarian Cancers

Recurrence-Free Interval Probabilities in Patients With Advanced-Stage (III and IV) BRCA-Associated (n=81) and Sporadic (n=100) Ovarian Cancers

A BRCA1/2 mutation is one of several prognostic factors for patients who have been diagnosed with epithelial ovarian cancer.21 The presence of a BRCA1/2 mutation has been found to predict a longer recurrence-free period than patients with sporadic cancers.22

Clinical Trial Eligibility

There are ongoing clinical trials specifically for patients with confirmed BRCA mutations.

List of active trials

Determination of the need for debulking surgery is made independently of the decision to test for a BRCA mutation. Testing for a BRCA mutation can take place before or after debulking surgery.

Response to Therapy

Response to Therapy

Loss of functional BRCA1/2 genes in ovarian tumor cells creates an increased sensitivity to DNA damage, including that from platinum-based chemotherapeutic agents.23 In addition, aberrant BRCA expression in tumor tissue samples has been linked to clinical benefit for the use of intraperitoneal chemotherapy compared with intravenous chemotherapy.24

Treatment-Free Interval

Treatment-Free Interval

A case-controlled analysis of 22 patients with epithelial ovarian cancer and a germline BRCA1/2 mutation showed a longer median treatment-free interval after standard therapy than in non-hereditary case-matched controls.21

Survival Outcomes

Survival Outcomes

Germline BRCA1/2 mutations are associated with improved survival, independent of the Federation of Gynecology and Obstetrics (FIGO) tumor stage and residual tumor volume after debulking surgery. A multivariate analysis shows that the presence of a BRCA1/2 mutation predicts increased survival in ovarian cancer (n=371).4

REFERENCES

1. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278(5340):1043–1105. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2015. 3. Ferla R, Calò V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18(suppl 6):vi93-vi98. 4. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180. 5. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473-2481. 6. National Cancer Institute. BRCA1 and BRCA2: Cancer risk and genetic testing. Fact sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA. 7. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 8. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 9. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series selected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 10. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 11. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. 12. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 13. Eichmeyer JN, Burnham C, Sproat P, Tivis R, Beck TM. The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. J Genet Couns. 2014;23(3):323-329. 14. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 15. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 16. King MC, Marks JH, Mandell JB; The New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):642-646. 17. Ford J. BRCA1 and BRCA2: Clinical genomics and target for therapeutics. Presented at: 2014 ASCO Annual Meeting, June 1, 2014. Chicago, IL. 18. Geier L. BRCA mutation carriers: how to find them, what to do with them. Presented at: 2013 Community Oncology Alliance Conference; March 20-23, 2013. 19. FORCE Web site. Understanding BRCA & HBOC > Finding Specialists & Paying for Care > Insurance & Financial Issues; http://www.facingourrisk.org. Accessed November 17, 2014. 20. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 21. Tan DSP, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530-5536. 22. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260-2265. 23. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 24. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. 25. Genetic Information Non-Discrimination Act, 42 USC § 2000ff-10 (2008).

Testing for BRCA1/2 mutation in patients diagnosed with ovarian cancer

About BRCA Testing

Information about testing options and patient counseling

Testing for a BRCA1/2 mutation in your patients diagnosed
with ovarian cancer

Testing can be done to identify either germline (hereditary) or somatic (tumor-specific) mutations in the BRCA1/2 genes. Germline analysis requires a sample of DNA from blood or saliva, and somatic mutations require a tumor tissue sample.

Single site testing

If a blood relative has tested positive for a deleterious BRCA1/2 mutation, the quickest and lowest cost procedure is to test for the single mutation that is known to be present in the family.

Comprehensive BRCA1/BRCA2 testing

Comprehensive BRCA1/BRCA2 testing includes full sequencing of BRCA1/BRCA2 and testing for large genomic rearrangements.

Gene panel testing

Gene panel testing can be used to simultaneously assess germline mutations in multiple genes that include but are not limited to BRCA1/BRCA2. Commercially available panels vary in the number of gene mutations tested and which genes are tested.

The Society of Gynecologic Oncology highlights the advantages and disadvantages of panel testing in a Clinical Practice Statement.

Genetic counseling

Pre-test and post-test counseling is essential for women to understand their genetic testing options and results.11 Testing and counseling should be performed by genetic counselors or other knowledgeable medical professionals, including oncologists and nurse practitioners, who have received adequate training and are up-to-date on the most current findings in cancer genetics.10

All patients undergoing genetic counseling should be fully engaged in informed consent, meaning that they are cognizant of the purpose of testing, information about the genes being tested, the implications of testing, and what will be done with the information acquired.10

Frequently, the counseling process (whether in office or by referral) requires multiple patient visits. Over that time, there can be a lack of patient follow-through, causing patients to drop out of the process.

In addition, if a patient’s test results are positive for a mutation of unknown significance, some laboratories may update the result and provide further information when and if a more definitive result is available.

Insurance coverage for BRCA1/2 mutation testing

Almost all insurance plans, including commercial, Medicare, and Medicaid plans, cover BRCA testing for patients diagnosed with ovarian cancer, regardless of the patient's family history or age. Coverage of BRCA testing for ovarian cancer patients is almost universal, unlike that for breast cancer, for which additional risk factors may be required for insurance coverage. The Genetic Information Non-Discrimination Act forbids discrimination on the basis of genetic information when it comes to any aspect of health insurance or employment.25

This information is for informational purposes only and is not provided as medical advice.

REFERENCES

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