Hereditary gynecologic cancers: risk assessment, counseling, testing and management

Gynecologists and gynecologic oncologists have a major role in identifying patients at increased risk of inherited cancer syndromes. Awareness of the biological and familial risk factors is useful in this practice, and can assist patients and families in navigating the follow-up for these complex disorders. Large national and international cohorts of women with known BRCA1/2 mutations or high risk continue to collect data in an attempt to better understand genetic risk, risk modifiers, and quality-of-life impact or screening, testing and risk reduction strategies. The Consortium of Investigators of Modifiers of BRCA1/2 is beginning to identify other genetic modifiers of BRCA1/2 risk and cancer cluster regions in an attempt to better individualize site specific cancer risk and prevention strategies. The Gynecologic Oncology Group has initiated along-term follow-up study to the Gynecologic Oncology Group 199 protocol, which will continue to advance understanding of patient decisions, quality-of-life impact, and other genetic factors responsible for cancer initiation and progression. These and other large consortia are invaluable resources with massive datasets requiring herculean analyses that will continue to rapidly advance our present knowledge and management of women with hereditary cancer syndromes.     

Hereditary predispositions to gynaecological cancers

The breast, ovary and endometrial cancers are hereditary in 5 to 10% of the cases. These genetic predisposition syndromes can be classified into two major classes: ovarian cancer and breast cancer predisposition family cases (genes BRCA1 and BRCA2) and family cases of colon cancer, endometrial cancer and ovarian cancer (Lynch syndrome or HNPCC) (genes hMLH1, hMSH2, hMLH6). The estimate of the family and individual risk can contribute in a determining manner to the management of these patients, by the practice of screening or an adapted prevention. Indeed, the risk of cancer of an individual having a positive test for a gene of predisposition to breast cancer (BRCA1, BRCA2) or to the colon cancer (hMLH1, hMSH2, hMLH6) lies between 50 and 70% at the age of 70 years. The indication of a genetic test must be discussed within the framework of an oncogenetic consultation. An individual and family medical management ranging from simple monitoring to prophylactic surgery is proposed to these predisposed people.     

Hereditary cancers in obstetrics and gynecology.

The lack of information regarding the effectiveness of screening strategies, chemoprevention, or surgical prophylaxis, and the uncertainty regarding penetrance and risk modification has led many experts to recommend that genetic testing for BRCA1, BRCA2, and other cancer susceptibility genes be performed only in a research setting. Patients, however, are likely to increasingly request access to genetic testing and deserve up-to-date counseling about recent advancements in our knowledge. The primary care physician should concentrate on identifying women likely to be at high-risk for cancer for further referral, allowing the cancer genetics specialist to track down medical records, clarify the pedigree, discuss genetic testing, and provide access to the appropriate cancer specialist to discuss risk reduction.     

Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program

PURPOSE: With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program. METHODS: Patients treated with either paclitaxel (P) or docetaxel (D) between 11/1999 and 8/2004 were identified through our pharmacy database. Records were reviewed and data collected on those patients who had a S-HSR, defined as symptoms for which drug was discontinued, to P, D, or both. RESULTS: 718 patients received P and 93 received D. 59 received D following treatment with P. The presence of S-HSR for P was 2.2% (16/718 patients) and for D was 9.7% (9/93 patients). 10 patients with S-HSR to P crossed over to D and all nine patients reacting to D had a prior reaction to T for a cross-sensitivity rate of 90% (9/10 patients). CONCLUSIONS: Cross-sensitivity of D after P was 90% at our institution. Given the different vehicles used in P and D, it is likely attributed to the taxane moiety. Caution is required with re-challenge of patients with docetaxel if they have previously reacted to paclitaxel.     

Modifying women's risk for cardiovascular disease

OBJECTIVE: To present current recommendations for cardiovascular disease risk reduction in women. DATA SOURCES: Medline databases were searched from 1990 to 2006 using keywords women and cardiovascular risk, hypertension, cholesterol, and hormone replacement therapy, as well as Web sites from scientific associations such as the American Heart Association, American College of Cardiology, Agency for Health Research and Quality, and the Centers for Disease Control for relevant scientific statements and guidelines. STUDY SELECTION: Randomized controlled trials, particularly those that have influenced current practice recommendations, scientific statements, and clinical practice guidelines were selected. DATA EXTRACTION AND SYNTHESIS: Factors contributing to women's particular risk and current practice recommendations. CONCLUSIONS: Current research has clarified the importance of regular exercise (at least 30 minutes/day most days of the week); abstinence from smoking; a diet focused on whole grains, fruits, vegetables, and low-fat protein sources; and maintenance of normal weight. This lifestyle combined with a partnership with a health care provider to maintain a normal blood pressure (115/75 mm Hg) and optimal lipoproteins through pharmacotherapy when indicated can prevent 82% of cardiovascular disease events in women.     

Hereditary ovarian cancer--assessing risk and prevention strategies

Hereditary ovarian cancers are almost entirely attributable to mutations in BRCA1/2 or the genes of DNA mismatch repair. Identifying individuals at risk requires a complete family history and evidence-guided genetic testing. Screening of women at increased risk for ovarian cancer can be considered in those not wishing prophylactic surgery and typically should include a twice-annual pelvic examination, serum CA-125 measurement, and transvaginal sonography. Patients must understand that these measures have not been conclusively proven to improve early detection or long-term survival. In all mutation carriers who have completed or do not desire childbearing, prophylactic bilateral salpingo-oophorectomy must be strongly considered.     

Hereditary carcinoma of the ovary and associated cancers: a study of two families

Increasing attention has been given to host factors in the etiology of ovarian carcinoma. Case/control studies have shown a significant excess of this disease among primary relatives of ovarian cancer affected. Pedigree studies have demonstrated its occurrence on a site-specific basis, in association with carcinoma of the breast (breast/ovarian carcinoma syndrome), and in other hereditary disorders. The complexity of this heterogeneity clearly warrants more intensive family studies. We have described genetic and clinicopathologic nuances in two extended ovarian cancer-prone families. The absence of premonitory physical stigmata and/or biomarkers which signify the cancer-prone genotype compels the physician to employ the best posits from the pedigree to identify those patients who are at inordinately high risk for ovarian and/or syndrome-associated cancer so that surveillance strategies can be more focused. Because of limitations of current surveillance strategies for the early detection of ovarian carcinoma, the clinician's responsibility includes the identification and counseling of candidates for prophylactic oophorectomy.     

Intrauterine factors and risk of nonepithelial ovarian cancers

Objective

The majority of ovarian tumors in girls and young women are nonepithelial in origin. The etiology of nonepithelial ovarian tumors remains largely unknown, and intrauterine exposures may play an important role. We examined the association of perinatal factors with risk of nonepithelial ovarian tumors in girls and young women.

Methods

National cohort study of 1,536,057 women born in Sweden during 1973–2004 and followed for diagnoses of nonepithelial ovarian tumors through 2009 (attained ages 5–37 years). Perinatal and maternal characteristics and cancer diagnoses were ascertained using nationwide health registry data.

Results

147 women were diagnosed with nonepithelial ovarian tumors in 31.6 million person-years of follow-up, including 94 with germ cell tumors and 53 with sex-cord stromal tumors. Women born preterm (< 37 weeks of gestation) had a significantly increased risk of developing nonepithelial ovarian tumors (adjusted hazard ratio 1.86, 95% CI 1.03–3.37; p = 0.04). Histological subgroup analyses showed that preterm birth was associated with increased risk of sex-cord stromal tumors (4.39, 2.12–9.10; p < 0.001), but not germ cell tumors (0.68, 0.21–2.15; p = 0.51). No significant associations were found with fetal growth, birth order, and maternal age at birth.

Conclusions

This large cohort study provides the first evidence that preterm birth is a risk factor for developing sex cord-stromal tumors. Ovarian hyperstimulation in response to high gonadotropin levels in preterm girls could mediate disease risk through the proliferative and steroidogenic effects of FSH and LH on granulosa and theca cells, from which most sex-cord stromal tumors are derived.     

The effects of male attractiveness and sexual attitudes on women's risk perception

This study examined the effects of male attractiveness, sexual attitudes, and victimization history on women's ratings of sexual risk. Women with more liberal sexual attitudes rated vignettes as less sexually risky than women with more conservative sexual attitudes. There was an interaction between situational risk and attractiveness, suggesting the relationship between attractiveness and sexual risk ratings varies across high and low situational risk. Findings emphasize the importance of using high and low risk situations to evaluate sexual risk perception and of investigating variables that may moderate women's risk perception.     

Strategies for the modification of risk factors in gynecological cancers

Strategies to modify risk for female or gynecological cancers will vary with our knowledge of the epidemiology, etiology, and specific molecular mechanisms for each individual cancer. In general, cancer preventive strategies have been divided into primary and secondary prevention with primary prevention directed toward the causative factors for a disease. Secondary prevention is classically used in cervical cancer cytology screening programs and is essentially an attempt to identify individuals in a population with preclinical phases of the disease where intervention will impact mortality the most. A vast literature has evolved regarding the epidemiology of most of the common cancers in women. While the specific molecular mechanisms are not completely understood at this time knowledge of contributing factors for many of these tumors is well known. The association of cigarette smoking with lung cancer has been well established and the increasing rates of lung cancer, particularly in women, are directly linked to the increasing number of female smokers in the population. Indeed in many western countries lung cancer deaths have overtaken breast cancer as the most common cause of death from malignant disease in women. Excessive sun exposure without adequate skin protection is another lifestyle activity that is related to the high incidence of skin cancer in certain areas. Epidemiologically, cervical cancer has been studied extensively with the current data indicating a causal role of exposure to human papillomavirus (HPV), particularly at an early age in this disease. Hereditary breast and ovarian cancer syndromes are well understood and as more information on human genomics becomes available a clear understanding of the underlying molecular mechanisms of these diseases will be possible and hopefully will result in effective strategies for their control. Unfortunately, in spite of the vast knowledge that is available regarding risk factors for many of these malignancies we have been unable to influence effective lifestyle changes that could substantially reduce the risk of these malignancies in our population. Increased efforts in education, research, and commitment--both financial and educational--are required by governments and other social organizations.     

Fertility drugs and the risk of breast and gynecologic cancers

The evaluation of cancer risk among patients treated for infertility is complex, given the need to consider indications for use, treatment details, and the effects of other factors (including parity status) that independently affect cancer risk. Many studies have had methodologic limitations. Recent studies that have overcome some of these limitations have not confirmed a link between drug use and invasive ovarian cancers, although there is still a lingering question as to whether borderline tumors might be increased. It is unclear whether this merely reflects increased surveillance. Investigations regarding breast cancer risk have produced inconsistent results. In contrast, an increasing number of studies suggest that fertility drugs may have a special predisposition for the development of uterine cancers, of interest given that these tumors are recognized as particularly hormonally responsive. Additional studies are needed to clarify the effects on cancer risk of fertility drugs, especially those used in conjunction with in vitro fertilization. Because many women who have received such treatments are still relatively young, further monitoring should be pursued in large well-designed studies that enable assessment of effects within a variety of subgroups defined by both patient and disease characteristics.     

Effect of autoimmune diseases on risk and survival in female cancers

Objectives

Patients with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited.

Methods

We analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIRs) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008.

Results

For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma.

Conclusions

Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks.     

Role of prophylactic hysterectomy in patients at high risk for hereditary cancers

BACKGROUND: Current surgical recommendations for ovarian cancer prophylaxis in women at high risk of developing ovarian cancer include bilateral salpingo-oophorectomy (risk-reducing salpingo-oophorectomy (RRSO)). The role of hysterectomy is unclear. We sought to determine outcomes following prophylactic surgery in high-risk women. METHODS: We surveyed unaffected members of the Gilda Radner Familial Ovarian Cancer Registry who had undergone oophorectomy from 1981 to 2002. Data were collected and analyzed for statistical significance by the Fisher's Exact Test. RESULTS: Two hundred eighty women were surveyed, and 154 (55%) responded; 97% were Caucasian and 14% reported being Jewish. The median age of the respondents was 51 years (range 29-79); median age at oophorectomy was 41 years (range 15-68). Fifty-eight patients (38%) reported a laparoscopic procedure. One hundred five patients (68%) had a simultaneous hysterectomy, and 4 (3%) had a prior hysterectomy. Forty-four patients (29%) underwent BSO only. Of these 44 patients, 40 (91%) did not require a subsequent hysterectomy. Of the 4 who did, 2 were for leiomyomas, one for menorrhagia and the other was unknown. While not statistically significant, of the 3 patients who developed a subsequent gynecologic malignancy, all had undergone a hysterectomy. There was a statistically significant difference in whether or not the uterus was removed as part of the procedure by time period, whereby women treated prior to 1990 had a higher likelihood of having a hysterectomy (P = 0.03). CONCLUSION: The women in our study did not require hysterectomy for prevention of malignancy. We conclude that one should screen for benign gynecological indications for hysterectomy when planning a prophylactic BSO for prevention of ovarian cancer. Other potential risk factors for endometrial cancer, including the role of UPSC in HBOC, remain to be elucidated.     

Retroperitoneal vascular aberrations increase the risk of vascular injury during lymphadenectomy in gynecologic cancers

Purpose

To investigate the frequency of aberrations of retroperitoneal great vessels in patients with gynecologic cancers who were scheduled for pelvic and paraaortic lymphadenectomy, and to document the vascular complications which occurred during lymphadenectomy as well as the relationship of these vascular complications with vascular aberrations.

Methods

Patients with gynecologic cancers underwent a routine preoperative abdominal multi-detector computer tomography, and an intraoperative search for aberrations of the great vessels in the retroperitoneal region was undertaken. Intraoperative vascular complications were recorded and their relations to vascular aberrations were analyzed.

Results

The rate of vascular aberrations detected preoperatively by multi-detector computed tomography was 24.3?%. Vascular injuries occurred in six patients (16.2?%) during lymphadenectomy. Rate of intraoperative vascular injuries was significantly higher in patients who had vascular aberrations of retroperitoneal great vessels (44.4 vs. 7.1?%, p?=?0.022).

Conclusions

Aberrations of retroperitoneal vessels are not uncommon and may increase the risk of vascular complications during lymphadenectomy. The risk of these complications may be decreased if aberrations are detected preoperatively.