Counseling Women at High Risk of Ovarian or Endometrial Cancer

ABSTRACT: Click here to link to the CME post-test for this article.

ABSTRACT: Certain women are at very high risk for developing ovarian and/or endometrial cancer. Although endometrial cancer tends to be diagnosed at an earlier stage and often can be managed successfully using a multimodality treatment regimen, ovarian cancer is typically diagnosed at an advanced stage, carrying a high mortality rate and causing more deaths than any other type of female reproductive cancer. About 10% of ovarian cancers are hereditary, with the majority attributable to BRCA1 and BRCA2 gene mutations. Whereas the average woman has a 1.7% lifetime risk of developing ovarian cancer, women with hereditary breast and ovarian cancer (HBOC) resulting from a BRCA1 or BRCA2 gene mutation have a lifetime ovarian cancer risk up to 44%. Potentially lifesaving cancer screening and prevention options can be offered to at-risk women who have undergone appropriate clinical testing and counseling. This article will describe the etiology of ovarian and endometrial cancer, personal histories and genetic factors that can place women at high-risk for these malignancies, screening modalities for ovarian and endometrial cancer, and preventive options.

The second most common gynecologic cancer among women, ovarian cancer causes more deaths than any other type of female reproductive cancer.[1] The average woman has a 1.7% lifetime risk of developing ovarian cancer, with the median age at onset being 63 years.[2] In contrast, women with hereditary breast and ovarian cancer resulting from a BRCA1 or BRCA2 gene mutation have a lifetime ovarian cancer risk up to 44%. The majority of ovarian cancers are sporadic, or nonhereditary. Only approximately 10% of ovarian cancer cases are hereditary.[3–5]

Ovarian cancer is difficult to detect early and is most commonly diagnosed at an advanced stage (stage III or IV). The overall 5-year survival rate of women with advanced ovarian cancer is only 20% to 30%. If ovarian cancer were detected in its early stages, however, the survival rate would improve significantly.[6] The difficulty is that the signs and symptoms of early-stage ovarian cancer are often vague, not specific to the disease, and may be attributed to other factors, such as a common bladder or digestive problem, often delaying the diagnosis. However, the symptoms of ovarian cancer tend to persist and worsen with time. As the cancer increases in size, symptoms may include pressure or pain in the abdomen, pelvis, back, or legs; a swollen or bloated abdomen; nausea, indigestion, gas, constipation, or diarrhea; and fatigue. Less common symptoms include shortness of breath, urinary urgency, and unusual vaginal bleeding (heavy periods or bleeding after menopause) (Table 1).[7] Ovarian cancer is frequently described as the “silent killer” because it often is diagnosed late in the disease trajectory, when the prognosis is poor.

TABLE 1

Signs and Symptoms of Ovarian and Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy, and the fourth most common cancer in women.[1] Diagnoses in women younger than 50 years of age have been linked to a number of risk factors, including obesity and hereditary cancer syndromes such as Lynch syndrome. The average woman has a 2% to 3% lifetime risk of endometrial cancer, as compared with a 40% to 60% risk of this malignancy in women with Lynch syndrome.[8–10] Endometrial cancer is highly curable if it is detected early. An endometrial biopsy, not a Pap smear, is necessary for the diagnosis of uterine cancer. The signs and symptoms of endometrial cancer include abnormal uterine bleeding; abnormal menstrual periods; bleeding between normal periods before menopause; vaginal bleeding or spotting after menopause; extremely long, heavy, or frequent episodes of vaginal bleeding after age 40; and lower abdominal pain or cramping accompanied by a thick white or clear vaginal discharge after menopause (Table 1).[11,12]

It is important to educate patients, especially those with a substantially increased risk of ovarian and endometrial cancer, to be aware of any symptoms suggestive of these cancers. Symptoms of ovarian cancer tend to be more severe and seem different compared with how a woman “usually” feels. Women are strongly encouraged to call their physicians, preferably their gynecologists, if these symptoms occur almost daily for more than a few weeks and cannot be explained by other more common conditions.

Hereditary Ovarian Cancer Syndromes

The majority of hereditary breast and ovarian cancers are attributable to deleterious mutations in the BRCA1 and BRCA2 genes.[13–15] A recent meta-analysis estimated the lifetime risk of breast cancer to be 47% to 66% in BRCA1 mutation carriers and 40% to 57% in BRCA2 mutation carriers. The ovarian cancer risk was estimated to be 35% to 46% in BRCA1 mutation carriers and 13% to 23% in BRCA2 mutation carriers.[13–18] Women with a BRCA1/BRCA2 mutation are at risk not only of developing ovarian cancer, but also fallopian tube and primary peritoneal cancer.[19] BRCA1 and BRCA2 mutations also have been associated with male breast cancer, prostate cancer, and pancreatic cancer.[13–18] The average age of onset of ovarian cancer in women with a BRCA1 mutation is 50.8 years and in women with a BRCA2 mutation is 57.1 years.[16] Therefore, women with BRCA1 or BRCA2 mutations have a substantially higher risk of developing ovarian cancer at a younger age compared with the age at which sporadic ovarian cancer occurs among women in the general population.

When reviewing a patient’s personal and family history, there are several indicators of an increased risk of hereditary breast and ovarian cancer, including:

• multiple family members affected by early-onset breast cancer diagnosed before age 50 or ovarian cancer at any age;

• bilateral breast cancer;

• multiple primary cancers in an individual;

• male breast cancer; and

• Ashkenazi Jewish ancestry.[20]

TABLE 2

NCCN Hereditary Breast and/or Ovarian Cancer Syndrome Testing Criteria

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is another hereditary cancer syndrome associated with an increased risk for ovarian cancer, as well as cancer of the endometrium, colon and rectum, stomach, small bowel, ureter, and renal pelvis, with these risks attributable to mutations in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Women with Lynch syndrome have a 7% to 12% lifetime risk of ovarian cancer, a 40% to 60% lifetime risk of endometrial cancer, and a 30% to 52% lifetime risk of colon cancer.[8–10] Other, more rare, hereditary cancer predisposition syndromes increasing a woman’s risk of gynecologic cancers include Li Fraumeni syndrome,[21] Peutz-Jeghers syndrome,[22] and Cowden syndrome.[23]

Identification of High-Risk Patients

At MD Anderson Cancer Center (MDACC), patients are identified as potentially at-risk for a hereditary cancer syndrome by their treating physician and referred to a genetic counselor within the institution for an evaluation. Guidelines and a variety of criteria can be used to establish whether a patient is eligible for BRCA1 and BRCA2 genetic testing (Table 2).

National testing guidelines are utilized during the genetic consultation, at which point the patient’s personal and family histories are reviewed, a risk assessment is performed, hereditary cancers are discussed, and genetic testing (if appropriate) is recommended. If a family member has been diagnosed with cancer and is alive, it is recommended that he or she proceed with genetic testing prior to testing of an unaffected family member, in order to provide the most accurate information for the family. Based on genetic test results and/or a strongly suggestive family history of cancer, a patient may have an inherited risk of ovarian or endometrial cancer-and thus a substantially increased likelihood of developing these malignancies. If this is the case, then the patient is referred to be evaluated and managed in the high-risk ovarian cancer screening clinic.

TABLE 3

Eligibility Criteria for High-Risk Ovarian Screening

Eligibility criteria were established for the high-risk ovarian screening clinic at MDACC to limit patients seen in the clinic to women with a significantly increased risk of ovarian or endometrial cancer based on a deleterious mutation consistent with a hereditary predisposition cancer syndrome or a strongly suggestive family history (Table 3).

If a patient requests an appointment in the high-risk ovarian screening clinic but does not meet these eligibility criteria, she is first referred to a genetic counselor to confirm whether the patient is, in fact, at high risk of ovarian or endometrial cancer. A thorough family history is obtained and genetic testing may be recommended for the patient or family member(s) with a history of cancer. This enables the genetic counselor to more accurately determine the patient’s risk of cancer prior to referral to the high-risk ovarian cancer screening clinic and ensures that only patients who are truly at high risk are managed and followed.

High-Risk Ovarian Screening Management

There are two major options for managing women at increased risk: screening or risk-reducing surgery.[24–34] Currently, ovarian cancer screening tools are less than ideal and there are no data to support the efficacy of ovarian cancer screening in the general population.[25,26] Recommendations and practice guidelines published by the National Comprehensive Cancer Network (NCCN) are used to manage ovarian cancer risks in patients with family characteristics suggestive of hereditary breast and ovarian cancer syndrome, or HBOC (Table 4). For high-risk women followed at MDACC with ovaries intact, ovarian cancer screening includes a transvaginal ultrasound, CA-125 blood test, and pelvic exam every 6 months. Clinicians measure CA-125 levels at each patient visit to the high-risk clinic and monitor for changes in CA-125 over time. The transvaginal ultrasound is used to detect any abnormalities in the ovaries, such as hemorrhagic cysts, complex cysts, and free fluid in the pelvis. For patients with Lynch syndrome, screening for endometrial and ovarian cancer includes annual endometrial biopsy, transvaginal ultrasound, and a CA-125 blood test.

TABLE 4

NCCN Practice Guidelines in Oncology for Hereditary Breast and/or Ovarian Cancer

At a woman’s appointment in the high-risk screening clinic, results of the transvaginal ultrasound and CA-125 are reviewed with the patient. Each patient is educated and counseled about the management of her ovarian and/or endometrial cancer risk, as well as screening and/or prophylactic surgical recommendations. Our clinicians emphasize that ovarian cancer is difficult to detect and current screening tools for ovarian and endometrial cancer are limited.[25,26]

Multiple studies have illustrated that premenopausal women with a BRCA1/BRCA2 mutation substantially reduce their risk of ovarian cancer by 85% to 95% by undergoing a prophylactic bilateral salpingo-oophorectomy (BSO). In addition, prophylactic salpingo-oophorectomy in a premenopausal woman decreases her risk of breast cancer by 50% to 60%.[27–33] Women with a BRCA1/BRCA2 mutation are counseled to undergo risk-reducing surgery at age 35 to 40 years, or after childbearing is complete. One study demonstrated risk-reducing surgery was associated with a lower risk of ovarian cancer, breast cancer, and cancer-specific mortality.[30]

Women with a BRCA1/BRAC2 mutation who have undergone a salpingo-oophorectomy still have a low residual risk of primary peritoneal carcinoma (PPC). The lifetime risk of PPC after a BSO is estimated to be 1.1% in BRCA1/BRAC2 mutation carriers.[30] While there are no data to support screening after a prophylactic BSO, our clinicians recommend annual CA-125 screening after surgery.

When discussing risk-reducing surgery, timing of the surgery is an important consideration. A 40-year-old woman with a BRCA1 mutation has a 2.3% risk of developing ovarian cancer, and a 0.1% risk if she has a BRCA2 mutation.[18,34] The risk of ovarian cancer begins to increase dramatically in women after 40 years of age, so the urgency of risk-reducing surgery is lower in women younger than age 40. Our clinicians encourage high-risk women to complete childbearing prior to prophylactic surgery, if they want to start a family or have more children. They also consider the ages at ovarian cancer diagnosis in affected family members, using this information to guide the timing of prophylactic surgery. These factors are discussed with the patient at length and are used to determine the appropriate age at which a high-risk woman should undergo surgery.

The decision to undergo a prophylactic BSO is not an easy one for premenopausal women at high-risk of developing ovarian cancer. Women often have to balance the quality of life changes that can occur after BSO-menopausal symptoms including hot flashes, night sweats, vaginal dryness, mood swings, and osteoporosis-against the benefit of surgery in substantially reducing their risk of developing ovarian cancer.[35–37] We at MDACC provide patients with a decision-making resource, “Ovarian Cancer Risk-Reducing Surgery,” offered by the Family Risk Assessment Program at Fox Chase Cancer Center in Philadelphia. This pamphlet is easy to read and comprehend, and it is used frequently by our patients.

In our experience, patients have a variety of questions and concerns about the timing of surgery, whether their uterus should also be removed along with their ovaries, use of hormone replacement therapy (HRT) for menopausal symptoms, and possible sexual dysfunction after surgery. Total hysterectomy and BSO is recommended in patients with Lynch syndrome because it is an effective strategy for prevention of endometrial and ovarian cancer.[38] For patients with a BRCA1/BRCA2 mutation, the question of removal of the uterus is not as clear because they are not at high-risk to develop endometrial cancer as a result of their mutation. If the patient has a history of abnormal Pap smears or is taking tamoxifen, however, a total hysterectomy may be considered.[39]

HRT is a topic of discussion requiring patient education communicated by our high-risk physicians. Replacing estrogen and progesterone may relieve vasomotor symptoms, but it can also increase the risks for breast cancer. HRT is not usually prescribed to women with a personal history of breast cancer.[40] Venlafaxine (Effexor), an antidepressant, is often given to women who are unable to take synthetic hormones to relieve menopausal symptoms.[41–43] In addition, low-dose vaginal estrogen may be considered for vaginal dryness even if a patient has a history of breast cancer, as there is a low systemic absorption of estrogen when it is used in this manner. At MDACC, a sexual counselor on staff is available to meet with patients to discuss the effect that a BSO may have on sexual functioning, and how to cope with and manage these issues after surgery.

HBOC Case Study

FIGURE 1

Family history of cancer.

The patient, “KF,” presented to MDACC with a recent diagnosis of high-grade serous ovarian cancer diagnosed at age 45. Her family history was significant for a sister, 55 years old, who was diagnosed with breast cancer at the age of 49. KF underwent comprehensive BRCA1 and BRCA2 genetic testing and was identified as having a BRCA1 mutation. Her sister then tested positive for the BRCA1 mutation and proceeded with a prophylactic BSO. (See Figure 1.) Pathological review of the sister’s surgical specimen revealed an occult fallopian tube cancer. High-risk ovarian screening and risk-reduction surgery in KF’s sister benefited her by preventing a late-stage fallopian tube cancer.

Lynch Case Study

FIGURE 2

Family history of cancer.

The patient, “MP,” presented for a genetics consultation because her sister had been diagnosed with colon cancer at 39 years of age and her brother was diagnosed with bladder cancer at age 36 and colon cancer at age 50. MP’s brother was found to have an MSH2 mutation consistent with Lynch syndrome. MP and her sister subsequently underwent single-site MSH2 genetic testing for the familial mutation and were also found to have inherited the mutation. (See Figure 2.) She and her sister both had intact ovaries and uteri, therefore they needed increased surveillance because of their known increased risk of ovarian and endometrial cancer. Prior to their brother’s genetic evaluation, the family had not known about the cancer risks associated with Lynch syndrome and the benefits of increased cancer surveillance. Now, MP and her sister are able to be monitored for their ovarian and endometrial cancer risks associated with Lynch syndrome and can consider whether to undergo risk-reducing surgery.

Educating and Supporting At-Risk Patients

Patient education and counseling are essential in women at increased risk for ovarian and endometrial cancer. Women must be educated regarding the signs, symptoms, and risks associated with these cancers. These high-risk women should seek out medical professionals who can evaluate their risk for cancer and recommend high-risk screening and/or risk-reducing surgery if appropriate. Prophylactic surgery is a life-changing decision, so at-risk women considering surgery must be provided with as much information as possible.

There are multiple advantages of a high-risk cancer screening clinic: it offers up-to-date information about cancer screening and prevention while providing the patient with emotional and psychosocial support. Women are able to openly discuss their questions, fears, and concerns with their doctors and nurses and in so doing are empowered to make educated decisions about a variety of potentially life-changing risk-reduction options. Educational and advocacy resources can be provided to assist patients, such as information from “FORCE” (Facing Our Risks of Cancer Empowered; www.facingourrisk.org) and “Be Bright Pink” (www.bebrightpink.org), national nonprofit organizations devoted specifically to educating and supporting individuals with BRCA1/BRCA2 mutations. Novels written by patients who have a BRCA mutation, including “Pretty Is What Changes” and “Previvors,” are discussed with women at MDACC who have been identified as being at high risk for breast/ovarian cancer and who express interest in reading more about this condition from a patient’s perspective. In addition to receiving a variety of educational and informative materials, at-risk women are managed and followed closely in a screening clinic by a high-risk specialist, to prevent them from being lost to follow-up.

With adequate education, counseling, and resources, high-risk women are supported physically, mentally, and emotionally in living with a higher risk for developing a gynecologic cancer.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

This article contains reference to one drug approved by the USFood and Drug Administration (FDA) that is used in treating sideeffects of surgical menopause without using hormone-replacementtherapy. No non–FDA-approved investigational agents are mentioned.

References

1. Jemal A, Siegel R, Xu J, et al: Cancer Statistics, 2010. CA Cancer J Clin 60:277–300, 2010.

2. Surveillance, Epidemiology and End Results (SEER) Program website. http://seer.cancer.gov/

3. Risch HA, McLaughlin JR, Cole DE, et al: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in population series of 649 women with ovarian cancer. Am J Hum Genet 68(3):700–710, 2001.

4. Pal T, Permuth-Wey J, Betts JA, et al: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104(12):2807–2816, 2005.

5. Lux MP, Fasching PA, Beckmann MW: Hereditary breast and ovarian cancer: Review and future perspectives. J Mol Med(Berl) 84(1):16–28, 2006.

6. American Cancer Society: Can Ovarian Cancer Be Found Early? Available at: http://www.cancer.org/index.

7. Lancaster JM, Powell CB, Kauff ND, et al: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer. Gynecol Oncol 107:159–162, 2007.

8. Aarnio M, Sankila R, Pukkala E, et al: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81(2):214–218, 1999.

9. Watson P, Vasen HF, Mecklin JP, et al: The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123(2): 444–449, 2008.

10. Weissman SM, Bellcross C, Bittner CC, et al: Genetic counseling considerations in the evaluation of families for Lynch syndrome-A review. J Genet Counsel 20(1):5–19, 2011.

11. Sonoda Y, Barakat RR: Screening and the prevention of gynecologic cancer: endometrial cancer. Best Pract Res Clin Obstet Gynaecol 20(2):363–377, 2006.

12. Smith RA, Cokkinides V, Eyre HJ: Cancer screening in the United States, 2007: A review of current guidelines, practices, and prospects. CA Cancer J Clin 57(2):90–104, 2007.

13. King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646, 2003.

14. Narod SA, Ford D, Devilee P, et al: An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium. Am J Hum Genet 56(1):254–264, 1995.

15. Chen S, Iversen ES, Friebel T, et al: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24(6):863–871, 2006.

16. Zhang S, Royer R, Li S, et al: Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 121(2):353–357, 2011.

17. Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130, 2003.

18. Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25(11):1329–1333, 2007.

19. Levine D, Argenta P, Yee C, et al: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21(22):4222–4227, 2003.

20. Committee Opinion No. 477: The role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet Gynecol 117(3):742–746, 2011.

21. Gonzalez K, Noltner K, Buzin C, et al: Beyond Li Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol 27(8):1250–1256, 2009.

22. Latchford A, Phillips R: Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: Clinical aspects. Fam Cancer April 2011 [Epub ahead of print].

23. Pilarski R: Cowden syndrome: A critical review of the clinical literature. J Genet Counsel 18:13–27, 2009.

24. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA 273(6):491–497, 1995.

25. Gaarenstroom KN, van der Hiel B, Tollenaar RA, et al: Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study. Int J Gynecol Cancer 16(Suppl 1):54–59, 2006.

26. Stirling D, Evans DG, Pichert G, et al: Screening for familial ovarian cancer: Failure of current protocols to detect ovarian cancer at an early stage according to the International Federation of Gynecology and Obstetrics system. J Clin Oncol 23(24):5588–5596, 2005.

27. Schwartz M, Kaufman E, Peshkin B, et al: Bilateral prophylactic oophorectomy and ovarian cancer screening following BRCA1/BRCA2 mutation testing. J Clin Oncol 21(21):4034–4041, 2003.

28. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346(21):1609–1615, 2002.

29. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346(21):1616–1622, 2002.

30. Domchek S, Friebel T, Singer C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304(9):967–975, 2010.

31. Powell CB, Kenley E, Chen LM, et al: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: Role of serial sectioning in the detection of occult malignancy. J Clin Oncol 23(1):127–132, 2005.

32. Lu KH, Garber JE, Cramer DW, et al: Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy. J Clin Oncol 18(14):2728–2732, 2000.

33. Scheuer L, Kauff N, Robson M, et al: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20(5):1260–1268, 2002.

34. Dowdy S, Hartmann L: Management of Hereditary Ovarian Cancer. In: American Society of Clinical Oncology Educational Book: Patient and Survivor Care, 2007, pp 535–538. Available at: http://www.asco.org/ASCOv2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2007/07patient02.pdf

35. Madalinska J, Hollenstein J, Bleiker E, et al: Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23:6890–6898, 2005.

36. Robson M, Hensley M, Barakat R, et al: Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol 89(2):281–287, 2003.

37. Westin SN, Sun CC, Lu KH, et al: Satisfaction with ovarian carcinoma risk-reduction strategies among women at high risk for breast and ovarian carcinoma. Cancer 117(12):2659–2667, 2011.

38. Schmeler KM, Lynch HT, Lu KH, et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354(3):261–269, 2006.

39. Duffy DL, Antill YC, Stewart CJ, et al: Report of endometrial cancer in Australian BRCA1 and BRCA2 mutation-positive families. Twin Res Hum Genet 14(2):111–118, 2011.

40. Baber R, Hickey M, Kwik M: Therapy for menopausal symptoms during and after treatment for breast cancer: Safety considerations. Drug Saf 28(12):1085–1100, 2005.

41. Bordeleau L, Pritchard KI, Loprinzi CL, et al: Multicenter, randomized, cross-over clinical trial of venlafaxine versiu gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 28(35):5147–5152, 2010.

42. Kaplan M, Mahon S, Cope D, et al: Putting evidence into practice: Evidence-based interventions for hot flashes resulting from ancer therapies. Clin J Oncol Nurs 15(2):149–157, 2011.

43. Pachman DR, Jones JM, Loprinzi CL, et al: Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. Int J Women’s Health 2:123–135, 2010.

44. College of American Pathologists: Cancer Protocols and Checklists: Protocol for the Examination of Specimens From Patients With Carcinoma of the Ovary. Posted February 1, 2011. Available at: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Ovary_11protocol.pdf (copyright-protected; please refer to licensing information on CAP website)

45. Haile RW, Thomas DC, McGuire V, et al: BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 15(10):1863–1870, 2006.