**Criteria for recommending genetic testing:** Currently, there are no standard criteria for rec‐ ommending or referring someone for BRCA1 orBRCA2 mutation testing American Society of Clinical Oncology (ASCO) has published some guidelines for Genetic Testing of cancer patients and their families. ASCO also encourages Oncologists to assume the responsibility of genetics counseling with patients and their families. ASCO General recommendation as to indications for genetic testing in generally are the following: 1) When a person has a strong family history of cancer or very early age of onset of disease. 2) Test can be adequate‐ ly interpreted. 3) Result will influence medical management of the patient/family member. In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has breast or ovarian cancer. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members can be tested to see if they also have the mutation. Women who have a relative with a harmful BRCA1 or BRCA2 mu‐ tation and women who appear to be at increased risk of breast and/or ovarian cancer be‐ cause of their family history should consider genetic counseling to learn more about their potential risks and about BRCA1 and BRCA2 genetic tests.

ASCO Recommendation as to indications for genetic testing for Breast and Ovarian cancers are the following: 1) Family with more than two breast cancer cases and one or more cases of ovarian cancer diagnosed at any age. 2) Family with more than three breast cancer cases diagnosed before age 50. 3) Sister pairs with two of the following cancers diagnosed before age 50: two breast cancers; two ovarian cancers; or a breast and ovarian cancer.4) Relatives of individuals with breast cancer diagnosed before the age of 30.Despite the above recom‐ mendations, there are individuals who do not fit any of the above categories and yet like to be tested. Such individuals need to be counseled to determine the appropriateness of genetic testing [1-5, 9-17].

**Genetic counseling:** Genetic counseling is generally recommended before and after a genet‐ ic test. This counseling should be performed by a health care professional experienced in cancer genetics. Genetic counseling usually involves a risk assessment based on the individ‐ ual's personal and family medical history and discussions about the appropriateness of ge‐ netic testing, the specific test(s) that might be used and the technical accuracy of the test(s), the medical implications of a positive or a negative test result, the possibility that a test re‐ sult might not be informative (an ambiguous result), the psychological risks and benefits of genetic test results, and the risk of passing a mutation to children. In case genetic testing turns positive health care professional must explain to her that a positive test result indi‐ cates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, there‐ fore, has an increased risk of developing cancer. Women considering genetic testing must know in advance certain facts about the risk to develop Ovarian Cancer if the tests are posi‐ tive as well as the available prevention options. The lifetime risk for women who are BRCA1 carriers is about 40-50% and for BRCA2 carriers about 10-20%. The following information must be provided to genetic testing candidates according to the NCI. Women must know that in addition to family history, other environmental and lifestyle factors may increase their risk of ovarian cancer. Discussing their family history and personal risk factors with a doctor helps them to better understand their risk. People with a higher than average risk may benefit from genetic counseling, and the implementation of early detection and preven‐ tion strategies.

has the duty to take its role. He/she must consider if each patient with ovarian cancer is a candidate for genetic testing. Hereditary cancer syndromes have a major ethical, legal and psychological impact on the individual as well as family members and the caring physician. As a result, a careful counseling before, during and after the testing is necessary. There are

**Criteria for recommending genetic testing:** Currently, there are no standard criteria for rec‐ ommending or referring someone for BRCA1 orBRCA2 mutation testing American Society of Clinical Oncology (ASCO) has published some guidelines for Genetic Testing of cancer patients and their families. ASCO also encourages Oncologists to assume the responsibility of genetics counseling with patients and their families. ASCO General recommendation as to indications for genetic testing in generally are the following: 1) When a person has a strong family history of cancer or very early age of onset of disease. 2) Test can be adequate‐ ly interpreted. 3) Result will influence medical management of the patient/family member. In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has breast or ovarian cancer. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members can be tested to see if they also have the mutation. Women who have a relative with a harmful BRCA1 or BRCA2 mu‐ tation and women who appear to be at increased risk of breast and/or ovarian cancer be‐ cause of their family history should consider genetic counseling to learn more about their

ASCO Recommendation as to indications for genetic testing for Breast and Ovarian cancers are the following: 1) Family with more than two breast cancer cases and one or more cases of ovarian cancer diagnosed at any age. 2) Family with more than three breast cancer cases diagnosed before age 50. 3) Sister pairs with two of the following cancers diagnosed before age 50: two breast cancers; two ovarian cancers; or a breast and ovarian cancer.4) Relatives of individuals with breast cancer diagnosed before the age of 30.Despite the above recom‐ mendations, there are individuals who do not fit any of the above categories and yet like to be tested. Such individuals need to be counseled to determine the appropriateness of genetic

**Genetic counseling:** Genetic counseling is generally recommended before and after a genet‐ ic test. This counseling should be performed by a health care professional experienced in cancer genetics. Genetic counseling usually involves a risk assessment based on the individ‐ ual's personal and family medical history and discussions about the appropriateness of ge‐ netic testing, the specific test(s) that might be used and the technical accuracy of the test(s), the medical implications of a positive or a negative test result, the possibility that a test re‐ sult might not be informative (an ambiguous result), the psychological risks and benefits of genetic test results, and the risk of passing a mutation to children. In case genetic testing turns positive health care professional must explain to her that a positive test result indi‐ cates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, there‐ fore, has an increased risk of developing cancer. Women considering genetic testing must know in advance certain facts about the risk to develop Ovarian Cancer if the tests are posi‐ tive as well as the available prevention options. The lifetime risk for women who are BRCA1

many issues that one has to know before proceeding with the genetic testing.

142 Ovarian Cancer - A Clinical and Translational Update

potential risks and about BRCA1 and BRCA2 genetic tests.

testing [1-5, 9-17].

There can be benefits to genetic testing, whether a person receives a positive or a nega‐ tive result. The potential benefits of a negative result include a sense of relief and the possibility that special preventive checkups, tests, or surgeries may not be needed. A positive test result can bring relief from uncertainty and allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addi‐ tion, many people who have a positive test result may be able to participate in medical research that could, in the long run, help reduce deaths from breast cancer. The direct medical risks, or harms, of genetic testing are very small, but test results may have an effect on a person's emotions, social relationships, finances, and medical choices. People who receive a positive test result may feel anxious, depressed, or angry. They may choose to undergo preventive measures, such as prophylactic surgery, that have serious long-term implications and whose effectiveness is uncertain. People who receive a nega‐ tive test result may experience "survivor guilt," caused by the knowledge that they like‐ ly do not have an increased risk of developing a disease that affects one or more loved ones. Because genetic testing can reveal information about more than one family mem‐ ber, the emotions caused by test results can create tension within families. Test results can also affect personal choices, such as marriage and childbearing. Issues surrounding the privacy and confidentiality of genetic test results are additional potential risks.

Ovarian cancer may run in the family if first-degree relatives (mother, sisters, daughters) or many other family members (grandmothers, aunts, nieces, granddaughters) have had ovari‐ an cancer. If a woman's first-degree relatives developed ovarian cancer, her risk of ovarian cancer is about three times higher than the average woman's risk of ovarian cancer. The risk increases if other close relatives have had ovarian cancer. When using family history to as‐ sess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affect‐ ed with cancer. In addition, small family sizes, premature deaths, immigration and poor medical records may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported in‐ formation with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%. [1-5, 10,11]

However, **a positive test** result provides information only about a person's risk of develop‐ ing cancer. It cannot tell whether an individual will actually develop cancer or when. It must be stressed that not all women who inherit a harmful BRCA1 or BRCA2 mutation will devel‐ op breast or ovarian cancer. A positive genetic test result may have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person's relatives. Both men and women who inherit harmful BRCA1 or BRCA2 mutations, whether they develop cancer themselves or not, may pass the mutations on to their sons and daughters. However, not all children of people who have a harmful mu‐ tation will inherit the mutation. How a **negative test** result will be interpreted depends on whether or not someone in the tested person's family is known to carry a harmful BRCA1 or BRCA2 mutation. If someone in the family has a known mutation, testing other family mem‐ bers for the same mutation can provide information about their cancer risk. If a person tests negative for a known mutation in his or her family, it is unlikely that they have an inherited susceptibility to cancer associated with BRCA1 orBRCA2. Such a test result is called **a "true negative."** On the other hand having a true negative test result does not mean that a person will not develop cancer; it means that the person's risk of cancer is probably the same as that of people in the general population. In cases in which a family has a history of breast and/or ovarian cancer and no known mutation in BRCA1 or BRCA2 has been previously identified, a negative test result is not informative. It is not possible to tell whether an individual has a harmful BRCA1 or BRCA2 mutation that was not detected by testing and this is called a **"false negative test"** or whether the result is a true negative. In addition, it is possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test(s) used. If genetic testing shows a change in BRCA1 or BRCA2 that has not been previously associated with cancer in other people, the person's test result may be interpreted as **"ambiguous"** and the result is considered as uncertain. It is es‐ timated that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result. Because everyone has genetic differences that are not associat‐ ed with an increased risk of disease, it is sometimes not known whether a specific DNA change affects a person's risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 changes, we expect to learn more about these changes and cancer risk [1-5, 9-17].

primary prevention. Not all methods are appropriate for all patients, and potential ad‐ verse effects, complications, cost, and efficacy of these interventions must be considered and reviewed with patients before implementation. It must be stressed that having a particular genetic mutation linked to ovarian cancer cannot predict that a person will

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 145

**Cancer prevention** is action taken to lower the chance of getting cancer. By preventing can‐ cer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer. To prevent new cancers from starting, we must consider risk and protective factors. Anything that increases one person's chance of developing cancer is called a cancer risk factor; anything that decreases the chance of devel‐ oping cancer is called a cancer protective factor. Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower the risk but it does not mean that cancer will be avoided. Dif‐ ferent ways to prevent cancer are being studied, including: Changing lifestyle or eating hab‐ its, avoiding things known to cause cancer or taking medicines to treat a precancerous condition or to keep cancer from starting[1-5,18-29]. According to the NCI's PDQ cancer in‐ formation about **Ovarian cancer prevention** the following risk factors may **increase** the risk of ovarian cancer: Family history of ovarian cancer, inherited risk, hormone replacement therapy, fertility drugs, talc and obesity. Factors associated with a **decreased** risk of ovarian cancer include: (a) using oral contraceptives, (b) having and breastfeeding children, (c) hav‐ ing a bilateral tubal ligation or hysterectomy, and (d) having a prophylactic oophorectomy. Multiple studies have consistently demonstrated a decrease in ovarian cancer risk in women who take oral contraceptives. The protective association increases with the duration of oral contraceptive use and persists up to 25 years after discontinuing oral contraceptives. A re‐ view of the literature demonstrated a 10% to 12% decrease in risk associated with use for 1 year and an approximate 50% decrease after 5 years of use. This reduced risk was present among both nulliparous and parous women. A protective association between oral contra‐ ceptives and risk of ovarian cancer has been observed in most studies among women who carry a mutation in BRCA1 and BRCA2 genes but a population-based study did not observe an association between oral contraceptives and ovarian cancer, while parity was protective. There may be a slight increase in a woman's risk of breast cancer during the time she is tak‐ ing oral contraceptives. This risk decreases over time. Pregnancy and breastfeeding are linked to a decreased risk of ovarian cancer. Ovulation stops or occurs less often in women who are pregnant or breastfeeding and women who ovulate less often have a decreased risk of ovarian cancer. Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of Oral contracep‐ tives. Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. Ovarian cancer incidence rises in a linear fash‐ ion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families. Nulliparity is consistently associated with an increased

develop cancer. [1-5, 18-29].

**Genetic tests:** Several methods are available to test for BRCA1 and BRCA2 mutations. Most of these methods look for changes in BRCA1 and BRCA2 DNA. At least one method looks for changes in the proteins produced by these genes. Frequently, a combination of methods is used. A blood sample is needed for these tests. The blood is drawn in a laboratory, doc‐ tor's office, hospital, or clinic and then sent to a laboratory that specializes in the tests. It usu‐ ally takes several weeks or longer to get the test results. Genetic tests are expensive and this represents a major problem in every day practice.

#### **5. Management of women with mutated genes**

The options available today for women who have tested positive can be divided into secondary and primary prevention. Methods of secondary prevention, such as surveil‐ lance, attempt to diagnose cancers at an early stage, while primary prevention prevents cancer development. Chemoprevention and prophylactic oophorectomy are examples of primary prevention. Not all methods are appropriate for all patients, and potential ad‐ verse effects, complications, cost, and efficacy of these interventions must be considered and reviewed with patients before implementation. It must be stressed that having a particular genetic mutation linked to ovarian cancer cannot predict that a person will develop cancer. [1-5, 18-29].

social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person's relatives. Both men and women who inherit harmful BRCA1 or BRCA2 mutations, whether they develop cancer themselves or not, may pass the mutations on to their sons and daughters. However, not all children of people who have a harmful mu‐ tation will inherit the mutation. How a **negative test** result will be interpreted depends on whether or not someone in the tested person's family is known to carry a harmful BRCA1 or BRCA2 mutation. If someone in the family has a known mutation, testing other family mem‐ bers for the same mutation can provide information about their cancer risk. If a person tests negative for a known mutation in his or her family, it is unlikely that they have an inherited susceptibility to cancer associated with BRCA1 orBRCA2. Such a test result is called **a "true negative."** On the other hand having a true negative test result does not mean that a person will not develop cancer; it means that the person's risk of cancer is probably the same as that of people in the general population. In cases in which a family has a history of breast and/or ovarian cancer and no known mutation in BRCA1 or BRCA2 has been previously identified, a negative test result is not informative. It is not possible to tell whether an individual has a harmful BRCA1 or BRCA2 mutation that was not detected by testing and this is called a **"false negative test"** or whether the result is a true negative. In addition, it is possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test(s) used. If genetic testing shows a change in BRCA1 or BRCA2 that has not been previously associated with cancer in other people, the person's test result may be interpreted as **"ambiguous"** and the result is considered as uncertain. It is es‐ timated that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result. Because everyone has genetic differences that are not associat‐ ed with an increased risk of disease, it is sometimes not known whether a specific DNA change affects a person's risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 changes, we expect to learn more about these

**Genetic tests:** Several methods are available to test for BRCA1 and BRCA2 mutations. Most of these methods look for changes in BRCA1 and BRCA2 DNA. At least one method looks for changes in the proteins produced by these genes. Frequently, a combination of methods is used. A blood sample is needed for these tests. The blood is drawn in a laboratory, doc‐ tor's office, hospital, or clinic and then sent to a laboratory that specializes in the tests. It usu‐ ally takes several weeks or longer to get the test results. Genetic tests are expensive and this

The options available today for women who have tested positive can be divided into secondary and primary prevention. Methods of secondary prevention, such as surveil‐ lance, attempt to diagnose cancers at an early stage, while primary prevention prevents cancer development. Chemoprevention and prophylactic oophorectomy are examples of

changes and cancer risk [1-5, 9-17].

144 Ovarian Cancer - A Clinical and Translational Update

represents a major problem in every day practice.

**5. Management of women with mutated genes**

**Cancer prevention** is action taken to lower the chance of getting cancer. By preventing can‐ cer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer. To prevent new cancers from starting, we must consider risk and protective factors. Anything that increases one person's chance of developing cancer is called a cancer risk factor; anything that decreases the chance of devel‐ oping cancer is called a cancer protective factor. Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower the risk but it does not mean that cancer will be avoided. Dif‐ ferent ways to prevent cancer are being studied, including: Changing lifestyle or eating hab‐ its, avoiding things known to cause cancer or taking medicines to treat a precancerous condition or to keep cancer from starting[1-5,18-29]. According to the NCI's PDQ cancer in‐ formation about **Ovarian cancer prevention** the following risk factors may **increase** the risk of ovarian cancer: Family history of ovarian cancer, inherited risk, hormone replacement therapy, fertility drugs, talc and obesity. Factors associated with a **decreased** risk of ovarian cancer include: (a) using oral contraceptives, (b) having and breastfeeding children, (c) hav‐ ing a bilateral tubal ligation or hysterectomy, and (d) having a prophylactic oophorectomy. Multiple studies have consistently demonstrated a decrease in ovarian cancer risk in women who take oral contraceptives. The protective association increases with the duration of oral contraceptive use and persists up to 25 years after discontinuing oral contraceptives. A re‐ view of the literature demonstrated a 10% to 12% decrease in risk associated with use for 1 year and an approximate 50% decrease after 5 years of use. This reduced risk was present among both nulliparous and parous women. A protective association between oral contra‐ ceptives and risk of ovarian cancer has been observed in most studies among women who carry a mutation in BRCA1 and BRCA2 genes but a population-based study did not observe an association between oral contraceptives and ovarian cancer, while parity was protective. There may be a slight increase in a woman's risk of breast cancer during the time she is tak‐ ing oral contraceptives. This risk decreases over time. Pregnancy and breastfeeding are linked to a decreased risk of ovarian cancer. Ovulation stops or occurs less often in women who are pregnant or breastfeeding and women who ovulate less often have a decreased risk of ovarian cancer. Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of Oral contracep‐ tives. Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. Ovarian cancer incidence rises in a linear fash‐ ion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families. Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2mutation carriers. Risk may also be increased among women who have used fertility drugs, especially those who remain nulli‐ gravid. Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-pro‐ gesterone schedules [1-5].

mended as appropriate interventions for women at high risk of ovarian cancer in a National Institutes of Health consensus conference although they did concede that there was no evi‐ dence of efficacy. Indeed, multiple investigations have been performed that cast doubt on the efficacy of these interventions. For example, a recent study prospectively screened 1,110 women with increased risk of ovarian cancer with pelvic ultrasound and CA-125 measure‐ ments. About half of patients were at moderate risk of developing ovarian cancer, with a 4% to 10% lifetime risk and half were at high risk with more than 10% lifetime risk. Invasive ovarian cancer was diagnosed in 12 patients. Two patients had stage I disease, one had stage II, four had stage III, and one had stage IV. These screening techniques missed an additional two patients with stage III disease and one patient with stage IV ovarian cancer. Based on abnormal ultrasound findings, 29 additional women underwent surgery for what turned out to be benign processes. The positive predictive value was 17%, and the sensitivity was less than 50%. These screening techniques are especially problematic for premenopausal women (the cohort with BRCA mutations is of highest interest) in which the false-positive rate was 79%. The conclusion is that the use of pelvic ultrasound and CA-125 does not meet World Health Organization screening standards for women with an increased risk for ovari‐ an cancer. The advantages of surveillance include avoidance of premature menopause and the fact that there is no intervention for those without disease. It allows management with other techniques, which may be available in the future. However, surveillance does not pre‐ vent disease, and an objective assessment of the data on screening for ovarian cancer does not support the use of these modalities, even in patients at elevated risk. For women who have not finished childbearing or are deferring prophylactic oophorectomy for other rea‐ sons, current practice guidelines from the National Comprehensive Cancer Network recom‐ mends concurrent transvaginal ultrasound and CA-125 every 6 months starting at age 35 or 5 to 10 years earlier than the earliest ovarian cancer diagnosis in the family (and preferably days 1 to 10 of cycle for premenopausal women). If initiated, it is important for these women to understand the shortcomings of surveillance. They should be aware of the high likelihood of an abnormal scan in ovulating women, and also understand that a normal scan does not

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 147

guarantee absence of disease, even in the advanced stages [1-5, 18-29].

**Chemoprevention** involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. It has been postulated that incessant ovulation may be one mechanism by which ovarian cancer develops. Consis‐ tent with this theory is the observation that parity is associated with a reduction in risk. **The use of oral contraceptives** has also been shown to reduce ovarian cancer risk by as much as 50% in the general population. However, there have been relatively few investigations studying the effect of oral contraceptive use on ovarian cancer risk in women with BRCA mutations. Unfortunately, the available data are conflicting. In one retrospective investiga‐ tion of 451 patients with BRCA mutations, women who used oral contraceptives for 6 or more years had an odds ratio of ovarian cancer of 0.62 (95% confidence interval [CI], 0.35– 1.09). Although not a statistically significant reduction in risk, this study suggests that oral contraceptives may be an effective form of chemoprevention in carriers. In contrast, Modan et al performed a case-control study of 1,591 Jewish women, 257 of whom underwent genet‐ ic testing and were found to have a BRCA mutation. They did not find clear evidence of a

**Surveillance** means cancer **screening**, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable. **Screening,** looking for cancer before a person has any symp‐ toms, can help find cancer at an early stage and increase the chances for cure or prolong sur‐ vival. By the time symptoms appear, the disease may have begun to spread and treatment results are usually disappointing. Before recommending screening it is important to esti‐ mate women who have increased risk to develop ovarian cancer in order to suggest the proper screening tests, when to start screening and how often to repeat it. If screening tests are abnormal then the physician has to proceed to diagnostic tests. There are unfortunately no satisfactory standard screening tests for ovarian cancer. Family members of ovarian can‐ cer patients must be informed that tests that may detect ovarian cancer are the following: Pelvic examination, transvaginal ultrasound and CA-125 assay. Although screening for ovarian cancer has not been proven to decrease the death rate from the disease, this ap‐ proach is the only available screening today for the possible early diagnosis for Ovarian Cancer and this is what we must follow. Several biomarkers with potential application to ovarian cancer screening are under development but have not yet been validated or evaluat‐ ed for efficacy in early detection and mortality reduction. The Pap test, which is considered by many women as the "screening for Gynecological Cancer", may occasionally detect ma‐ lignant ovarian cells, but it is not sensitive, the reported sensitivity is about 10%–30%, and has not been evaluated for the early detection of ovarian cancer. Other methods of detection, including cytologic examination of peritoneal lavage obtained by culdocentesis and proteo‐ mics used to identify patterns or specific serum markers that may be used in place of, or in conjunction with, CA 125 measurements remain under study. Given the low incidence of ovarian cancer in the general population, the use of these modalities has not been adopted for screening purposes in the general population. To be cost effective and avoid unnecessary surgical interventions, the use of transvaginal ultrasound and CA-125 would need to be nearly 100% specific and sensitive. Premenopausal women in particular have a high inci‐ dence of benign ovarian cysts. Although CA-125 can be a reliable marker for recurrence in women with a previous diagnosis of ovarian cancer, only 50% of early-stage ovarian cancers are associated with an abnormal CA-125. It must be noted that CA-125 can also show spuri‐ ous elevations in association with any process, which irritates the peritoneal or pleural cavi‐ ty, such as endometriosis, pneumonia, pulmonary embolism, or even normal menses. Prospective screening trials, using ultrasound and CA-125, in women in the general popula‐ tion have resulted in approximately 30 surgeries for every cancer diagnosed and have failed to detect disease at an early stage. Given the higher prevalence of ovarian cancer in patients with BRCA mutations, there has been speculation that pelvic ultrasound and CA-125 may be useful screening strategies for these patients. In fact, annual or semiannual screening with pelvic examination, transvaginal ultrasonography, and serum CA-125 was recom‐ mended as appropriate interventions for women at high risk of ovarian cancer in a National Institutes of Health consensus conference although they did concede that there was no evi‐ dence of efficacy. Indeed, multiple investigations have been performed that cast doubt on the efficacy of these interventions. For example, a recent study prospectively screened 1,110 women with increased risk of ovarian cancer with pelvic ultrasound and CA-125 measure‐ ments. About half of patients were at moderate risk of developing ovarian cancer, with a 4% to 10% lifetime risk and half were at high risk with more than 10% lifetime risk. Invasive ovarian cancer was diagnosed in 12 patients. Two patients had stage I disease, one had stage II, four had stage III, and one had stage IV. These screening techniques missed an additional two patients with stage III disease and one patient with stage IV ovarian cancer. Based on abnormal ultrasound findings, 29 additional women underwent surgery for what turned out to be benign processes. The positive predictive value was 17%, and the sensitivity was less than 50%. These screening techniques are especially problematic for premenopausal women (the cohort with BRCA mutations is of highest interest) in which the false-positive rate was 79%. The conclusion is that the use of pelvic ultrasound and CA-125 does not meet World Health Organization screening standards for women with an increased risk for ovari‐ an cancer. The advantages of surveillance include avoidance of premature menopause and the fact that there is no intervention for those without disease. It allows management with other techniques, which may be available in the future. However, surveillance does not pre‐ vent disease, and an objective assessment of the data on screening for ovarian cancer does not support the use of these modalities, even in patients at elevated risk. For women who have not finished childbearing or are deferring prophylactic oophorectomy for other rea‐ sons, current practice guidelines from the National Comprehensive Cancer Network recom‐ mends concurrent transvaginal ultrasound and CA-125 every 6 months starting at age 35 or 5 to 10 years earlier than the earliest ovarian cancer diagnosis in the family (and preferably days 1 to 10 of cycle for premenopausal women). If initiated, it is important for these women to understand the shortcomings of surveillance. They should be aware of the high likelihood of an abnormal scan in ovulating women, and also understand that a normal scan does not guarantee absence of disease, even in the advanced stages [1-5, 18-29].

risk of ovarian cancer, including among BRCA1/BRCA2mutation carriers. Risk may also be increased among women who have used fertility drugs, especially those who remain nulli‐ gravid. Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-pro‐

**Surveillance** means cancer **screening**, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable. **Screening,** looking for cancer before a person has any symp‐ toms, can help find cancer at an early stage and increase the chances for cure or prolong sur‐ vival. By the time symptoms appear, the disease may have begun to spread and treatment results are usually disappointing. Before recommending screening it is important to esti‐ mate women who have increased risk to develop ovarian cancer in order to suggest the proper screening tests, when to start screening and how often to repeat it. If screening tests are abnormal then the physician has to proceed to diagnostic tests. There are unfortunately no satisfactory standard screening tests for ovarian cancer. Family members of ovarian can‐ cer patients must be informed that tests that may detect ovarian cancer are the following: Pelvic examination, transvaginal ultrasound and CA-125 assay. Although screening for ovarian cancer has not been proven to decrease the death rate from the disease, this ap‐ proach is the only available screening today for the possible early diagnosis for Ovarian Cancer and this is what we must follow. Several biomarkers with potential application to ovarian cancer screening are under development but have not yet been validated or evaluat‐ ed for efficacy in early detection and mortality reduction. The Pap test, which is considered by many women as the "screening for Gynecological Cancer", may occasionally detect ma‐ lignant ovarian cells, but it is not sensitive, the reported sensitivity is about 10%–30%, and has not been evaluated for the early detection of ovarian cancer. Other methods of detection, including cytologic examination of peritoneal lavage obtained by culdocentesis and proteo‐ mics used to identify patterns or specific serum markers that may be used in place of, or in conjunction with, CA 125 measurements remain under study. Given the low incidence of ovarian cancer in the general population, the use of these modalities has not been adopted for screening purposes in the general population. To be cost effective and avoid unnecessary surgical interventions, the use of transvaginal ultrasound and CA-125 would need to be nearly 100% specific and sensitive. Premenopausal women in particular have a high inci‐ dence of benign ovarian cysts. Although CA-125 can be a reliable marker for recurrence in women with a previous diagnosis of ovarian cancer, only 50% of early-stage ovarian cancers are associated with an abnormal CA-125. It must be noted that CA-125 can also show spuri‐ ous elevations in association with any process, which irritates the peritoneal or pleural cavi‐ ty, such as endometriosis, pneumonia, pulmonary embolism, or even normal menses. Prospective screening trials, using ultrasound and CA-125, in women in the general popula‐ tion have resulted in approximately 30 surgeries for every cancer diagnosed and have failed to detect disease at an early stage. Given the higher prevalence of ovarian cancer in patients with BRCA mutations, there has been speculation that pelvic ultrasound and CA-125 may be useful screening strategies for these patients. In fact, annual or semiannual screening with pelvic examination, transvaginal ultrasonography, and serum CA-125 was recom‐

gesterone schedules [1-5].

146 Ovarian Cancer - A Clinical and Translational Update

**Chemoprevention** involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. It has been postulated that incessant ovulation may be one mechanism by which ovarian cancer develops. Consis‐ tent with this theory is the observation that parity is associated with a reduction in risk. **The use of oral contraceptives** has also been shown to reduce ovarian cancer risk by as much as 50% in the general population. However, there have been relatively few investigations studying the effect of oral contraceptive use on ovarian cancer risk in women with BRCA mutations. Unfortunately, the available data are conflicting. In one retrospective investiga‐ tion of 451 patients with BRCA mutations, women who used oral contraceptives for 6 or more years had an odds ratio of ovarian cancer of 0.62 (95% confidence interval [CI], 0.35– 1.09). Although not a statistically significant reduction in risk, this study suggests that oral contraceptives may be an effective form of chemoprevention in carriers. In contrast, Modan et al performed a case-control study of 1,591 Jewish women, 257 of whom underwent genet‐ ic testing and were found to have a BRCA mutation. They did not find clear evidence of a protective effect with oral contraceptive use in BRCA carriers. Given the low incidence of adverse effects, before more definitive investigations are available, the use of oral contracep‐ tives as a chemopreventive strategy would appear to be a reasonable approach for the pa‐ tient who declines prophylactic salpingo-oophorectomy and for whom prevention of pregnancy is acceptable. However, the conflicting data should be reviewed with the patient before initiation [1-5, 18-29].

was a 47% reduction in the risk of breast cancer in premenopausal women who had prophy‐ lactic salpingo-oophorectomy. The effectiveness of prophylactic salpingo-oophorectomy in reduction of ovarian cancer risk has also been demonstrated in prospective studies. Prophy‐ lactic salpingo-oophorectomy failures may be divided into groups of those patients who are found to harbor an occult malignancy at the time of surgery and those who go on to develop carcinoma at a later time. The existence of occult ovarian cancer in BRCA carriers with appa‐ rently healthy ovaries has been documented in small samples for a number of years. In a recent investigation that included 555 women who underwent prophylactic salpingo-oopho‐ rectomy, the rate of occult fallopian tube or ovarian cancer was 2.2%, consistent with prior reports. Although a low incidence, this risk should routinely be discussed with patients be‐ fore surgery and highlights the need for an extensive pathologic assessment of the entire ad‐ nexa, including the fallopian tubes [30-43]. Development of primary peritoneal carcinoma (PPC) represents the vast majority of failures after prophylactic salpingo-oophorectomy. In a multicenter investigation of 1,828 carriers, the cumulative risk of PPC was 4.3% at 20 years after prophylactic salpingo-oophorectomy.24 It is hypothesized that PPC arises from the peritoneal coelomic epithelium, derived from the same embryonic tissue that gives rise to the epithelial covering of the ovaries. Ovarian and peritoneal epithelium share common em‐ bryonal origin, originating both from the coelomic epithelium (mesodermal origin). Coelo‐ mic epithelium is thought to be of mesonephric origin. With the overall point being that normal ovarian and peritoneal tissue is derived from the mesonephros. On the contrary, fal‐ lopian tube epithelium, endometrium and endocervix are related to paramesonephros (Mül‐ lerian duct). Surprisingly, epithelial ovarian cancer and primary peritoneal cancer are histologically similar to the Mullerian epithelium; not their embryonal origin, the meso‐ nephros. Either a metaplasia has occurred or Mullerian remnants have been left behind in coelemic epithelium, which have turned oncogenic. Although the precise causes are not known, a link with certain variants of BRCA1/2 has been described. Furthermore, women with BRCA1/2 mutation have a 5% risk of developing primary peritoneal cancer even after prophylactic oophorectomy. Primary peritoneal carcinoma shows similar rates of tumor suppressor gene dysfunction (p53, BRCA, WT1) as ovarian cancer and can also show an in‐ creased expression of HER-2/neu. An association with vascular endothelial growth factor has been observed. Although the absolute risk of fallopian tube cancer is unknown in pa‐ tients with BRCA mutations, it is agreed that it is substantially elevated, with a relative risk of 120 in one study. It remains unknown if the 4.3% failure rate found by Finch et al consists entirely of PPC or if a proportion is in fact peritoneal recurrences of a fallopian tube carcino‐ ma missed at the time of prophylactic salpingo-oophorectomy. Regardless, it is widely ac‐ cepted that removal of the fallopian tubes is essential at the time of prophylactic surgery. There is an abundance of evidence supporting the efficacy of prophylactic salpingo-oopho‐ rectomy, but less information exists to counsel the clinician as to the optimal timing of pro‐ phylactic surgery. Reasonable guidelines can be inferred from existing data regarding the onset of ovarian cancer in BRCA carriers. The cumulative incidence of breast cancer is 11.6% by age 40 for women with BRCA1 mutations. In contrast, the rate is only 2.3% for ovarian cancer by age 40. By age 45, 6.5% of BRCA1 carriers will be diagnosed with ovarian cancer; 13.2% by age 50. As a result, for BRCA1 carriers, most physicians recommend prophylactic

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 149

**Prophylactic salpingo-oophorectomy.** The use of oral contraceptives, having and breast‐ feeding children do not certainly offer enough protection for BRCA1/BRCA2 carriers. The removal of the "at-risk" tissue is the most important step to prevent Ovarian Cancer. Wom‐ en who have a high risk of ovarian cancer must be informed about the possibility of a pro‐ phylactic oophorectomy. This includes women who have inherited certain changes in the BRCA1 and BRCA2 genes or in the genes linked to hereditary nonpolyposis colon cancer (HNPCC). It is very important to have a cancer risk assessment and counseling before mak‐ ing this decision. These and other factors should be discussed: Early menopause: 90% reduc‐ tion in risk of ovarian cancer observed among women with a BRCA1 or BRCA2 mutation. BRCA1 or BRCA2 mutations occur in 0.1–0.8% of the general population and are inherited in an autosomal dominant manner. They are well recognized to have a higher incidence in certain ethnic groups, such as women of Ashkenazi Jewish descent. S Vaughan Given the newly appreciated importance of the fallopian tube in the genesis of high-grade serous ovar‐ ian cancer, it is recommended that the complete removal of the fallopian tube should be‐ come standard of care in any woman undergoing hysterectomy and/or removal of the ovaries (oophorectomy). Oophorectomy in premenopausal women induces early meno‐ pause. As a consequence, and with the changed view of the role of the fallopian tube in ovarian cancer, some clinicians have recommended that only the fallopian tubes should be removed (salpingectomy) in women with germline BRCA1 or BRCA2 mutations, or in wom‐ en with a strong family history of breast and/or ovarian cancer34. However, until compre‐ hensive comparative data are available, it is premature to recommend that only the fallopian tubes are removed in high-risk women [1-5, 30-43].

Women who have completed childbearing are candidates for surgery. For the majority of women, this surgery can be performed laparoscopically as an outpatient procedure. In con‐ trast to surveillance and chemoprevention, this intervention is very effective in reducing the risk of ovarian cancer. Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. Ovarian cancer risk is re‐ duced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. In a retrospective analysis of 551 patients, Rebbeck et al showed that women who had under‐ gone prophylactic salpingo-oophorectomy had an odds ratio of 0.04 for ovarian cancer, com‐ pared with carriers without prophylactic salpingo-oophorectomy. Over a median follow-up of 8.8 years, two primary peritoneal cancers were diagnosed in the 259 women who under‐ went prophylactic salpingo-oophorectomy compared with 58 ovarian/peritoneal cancers in the 292 women who did not have prophylactic salpingo-oophorectomy. An added benefit was a 47% reduction in the risk of breast cancer in premenopausal women who had prophy‐ lactic salpingo-oophorectomy. The effectiveness of prophylactic salpingo-oophorectomy in reduction of ovarian cancer risk has also been demonstrated in prospective studies. Prophy‐ lactic salpingo-oophorectomy failures may be divided into groups of those patients who are found to harbor an occult malignancy at the time of surgery and those who go on to develop carcinoma at a later time. The existence of occult ovarian cancer in BRCA carriers with appa‐ rently healthy ovaries has been documented in small samples for a number of years. In a recent investigation that included 555 women who underwent prophylactic salpingo-oopho‐ rectomy, the rate of occult fallopian tube or ovarian cancer was 2.2%, consistent with prior reports. Although a low incidence, this risk should routinely be discussed with patients be‐ fore surgery and highlights the need for an extensive pathologic assessment of the entire ad‐ nexa, including the fallopian tubes [30-43]. Development of primary peritoneal carcinoma (PPC) represents the vast majority of failures after prophylactic salpingo-oophorectomy. In a multicenter investigation of 1,828 carriers, the cumulative risk of PPC was 4.3% at 20 years after prophylactic salpingo-oophorectomy.24 It is hypothesized that PPC arises from the peritoneal coelomic epithelium, derived from the same embryonic tissue that gives rise to the epithelial covering of the ovaries. Ovarian and peritoneal epithelium share common em‐ bryonal origin, originating both from the coelomic epithelium (mesodermal origin). Coelo‐ mic epithelium is thought to be of mesonephric origin. With the overall point being that normal ovarian and peritoneal tissue is derived from the mesonephros. On the contrary, fal‐ lopian tube epithelium, endometrium and endocervix are related to paramesonephros (Mül‐ lerian duct). Surprisingly, epithelial ovarian cancer and primary peritoneal cancer are histologically similar to the Mullerian epithelium; not their embryonal origin, the meso‐ nephros. Either a metaplasia has occurred or Mullerian remnants have been left behind in coelemic epithelium, which have turned oncogenic. Although the precise causes are not known, a link with certain variants of BRCA1/2 has been described. Furthermore, women with BRCA1/2 mutation have a 5% risk of developing primary peritoneal cancer even after prophylactic oophorectomy. Primary peritoneal carcinoma shows similar rates of tumor suppressor gene dysfunction (p53, BRCA, WT1) as ovarian cancer and can also show an in‐ creased expression of HER-2/neu. An association with vascular endothelial growth factor has been observed. Although the absolute risk of fallopian tube cancer is unknown in pa‐ tients with BRCA mutations, it is agreed that it is substantially elevated, with a relative risk of 120 in one study. It remains unknown if the 4.3% failure rate found by Finch et al consists entirely of PPC or if a proportion is in fact peritoneal recurrences of a fallopian tube carcino‐ ma missed at the time of prophylactic salpingo-oophorectomy. Regardless, it is widely ac‐ cepted that removal of the fallopian tubes is essential at the time of prophylactic surgery. There is an abundance of evidence supporting the efficacy of prophylactic salpingo-oopho‐ rectomy, but less information exists to counsel the clinician as to the optimal timing of pro‐ phylactic surgery. Reasonable guidelines can be inferred from existing data regarding the onset of ovarian cancer in BRCA carriers. The cumulative incidence of breast cancer is 11.6% by age 40 for women with BRCA1 mutations. In contrast, the rate is only 2.3% for ovarian cancer by age 40. By age 45, 6.5% of BRCA1 carriers will be diagnosed with ovarian cancer; 13.2% by age 50. As a result, for BRCA1 carriers, most physicians recommend prophylactic

protective effect with oral contraceptive use in BRCA carriers. Given the low incidence of adverse effects, before more definitive investigations are available, the use of oral contracep‐ tives as a chemopreventive strategy would appear to be a reasonable approach for the pa‐ tient who declines prophylactic salpingo-oophorectomy and for whom prevention of pregnancy is acceptable. However, the conflicting data should be reviewed with the patient

**Prophylactic salpingo-oophorectomy.** The use of oral contraceptives, having and breast‐ feeding children do not certainly offer enough protection for BRCA1/BRCA2 carriers. The removal of the "at-risk" tissue is the most important step to prevent Ovarian Cancer. Wom‐ en who have a high risk of ovarian cancer must be informed about the possibility of a pro‐ phylactic oophorectomy. This includes women who have inherited certain changes in the BRCA1 and BRCA2 genes or in the genes linked to hereditary nonpolyposis colon cancer (HNPCC). It is very important to have a cancer risk assessment and counseling before mak‐ ing this decision. These and other factors should be discussed: Early menopause: 90% reduc‐ tion in risk of ovarian cancer observed among women with a BRCA1 or BRCA2 mutation. BRCA1 or BRCA2 mutations occur in 0.1–0.8% of the general population and are inherited in an autosomal dominant manner. They are well recognized to have a higher incidence in certain ethnic groups, such as women of Ashkenazi Jewish descent. S Vaughan Given the newly appreciated importance of the fallopian tube in the genesis of high-grade serous ovar‐ ian cancer, it is recommended that the complete removal of the fallopian tube should be‐ come standard of care in any woman undergoing hysterectomy and/or removal of the ovaries (oophorectomy). Oophorectomy in premenopausal women induces early meno‐ pause. As a consequence, and with the changed view of the role of the fallopian tube in ovarian cancer, some clinicians have recommended that only the fallopian tubes should be removed (salpingectomy) in women with germline BRCA1 or BRCA2 mutations, or in wom‐ en with a strong family history of breast and/or ovarian cancer34. However, until compre‐ hensive comparative data are available, it is premature to recommend that only the fallopian

Women who have completed childbearing are candidates for surgery. For the majority of women, this surgery can be performed laparoscopically as an outpatient procedure. In con‐ trast to surveillance and chemoprevention, this intervention is very effective in reducing the risk of ovarian cancer. Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. Ovarian cancer risk is re‐ duced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. In a retrospective analysis of 551 patients, Rebbeck et al showed that women who had under‐ gone prophylactic salpingo-oophorectomy had an odds ratio of 0.04 for ovarian cancer, com‐ pared with carriers without prophylactic salpingo-oophorectomy. Over a median follow-up of 8.8 years, two primary peritoneal cancers were diagnosed in the 259 women who under‐ went prophylactic salpingo-oophorectomy compared with 58 ovarian/peritoneal cancers in the 292 women who did not have prophylactic salpingo-oophorectomy. An added benefit

before initiation [1-5, 18-29].

148 Ovarian Cancer - A Clinical and Translational Update

tubes are removed in high-risk women [1-5, 30-43].

salpingo-oophorectomy between ages 35 to 40 years. However, performing prophylactic sal‐ pingo-oophorectomy before age 45 must be considered in the context of the potential mor‐ bidity of estrogen deprivation at an early age. Oophorectomy before age 45 has been associated with a hazard ratio of 1.96 for death from all causes (p 0.002). However, adminis‐ tration of estrogen replacement eliminated this risk. Many physicians consider estrogen therapy for women without a personal history of breast cancer who undergo prophylactic salpingo-oophorectomy before the age of 45.29 It should be noted that early prophylactic salpingo-oophorectomy is less important for BRCA2 carriers who are known to develop ovarian cancer at approximately the same age as patients with sporadic cancer. Only 1.2% of BRCA2 carriers will have ovarian cancer by the age of 50, so prophylactic salpingo-oopho‐ rectomy may safely be delayed until these patients are closer to menopause. The disadvan‐ tages of prophylactic salpingo-oophorectomy include the fact that it is an invasive surgical intervention, there is loss of ovarian tissue with accompanying hormone deprivation, and it is an irreversible decision. However, in contrast to surveillance and chemoprevention, pro‐ phylactic salpingo-oophorectomy has proven efficacy over an extended time period. Cost analyses comparing surveillance, oral contraceptives, and prophylactic salpingo-oophorec‐ tomy have shown that although any primary prevention strategy was cost effective, prophy‐ lactic salpingo-oophorectomy dominated all other strategies in women with BRCA mutations. Consequently, prophylactic salpingo-oophorectomy is recommended for all BRCA carriers, with timing dependent on the type of BRCA1 or BRCA2 mutation, childbear‐ ing status, and the age of onset of ovarian cancer within the family. The resultant physical and emotional outcomes of repeated gynecological screening or prophylactic oophorectomy must be discussed before and after genetic testing. A study of 315 women with documented HNPCC–associated germline mutations found no ovarian cancer among 47 women who had bilateral salpingo-oophorectomy and 12 cases (5%) among women with mutations who had not had surgery for a prevented fraction of 100% (95% CI, 62%–100%).

**6. Treatment**

lapses and improved overall survival [44].

Over the past ten years, the focus of management for BRCA1/2mutation carriers has been on cancer prevention and early cancer detection. However, despite prophylactic measures to reduce risk of EOC, many BRCA1/2 carriers have cancer at the time their mutation is diag‐ nosed and more will develop in the future. The treatment of patients with BRCA associated EOC is so far identical to those with sporadic disease. Data suggested that cancers associat‐ ed with BRCA mutations responded differently to chemotherapy. Tan et al. compared 22 BRCA-positive patients with EOC to 44 nonhereditary EOC controls in a matched case-con‐ trol study. They found that BRCA-positive patients have higher response rates to first line platinum-based treatment (81.8%versus 43.2%, P =.004) as well as to subsequent lines of platinum-based treatments (second line, 91.7% versus 40.9%, P =.004), third line, 100% v 14,3% (P<. 002) and time of first relapse (5v 1.6 years; P<. 001). They conclude that BRCApositive EOC patients have better outcomes than nonhereditary EOC cases. There exists a clinical syndrome of BRCAness that includes serous histology, high response rates to first and subsequent lines of platinum-based treatment, longer tumor free interval between re‐

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 151

Over recent years the investigation of DNA repair in cancer cells has been a very active area of translational research. All cells have a number of overlapping pathways to protect the ge‐ nome from DNA damage, which occurs as a result of normal cell cycling, environmental in‐ sults, or cytotoxic chemotherapy. It is well recognized that when mutations occur within these DNA repair pathways there is an increased risk of malignant transformation and che‐ motherapy resistance. Much research has focused on protecting cells from DNA damage and/or restoring DNA repair function. However, emerging data suggest that the concept of "synthetic lethality," that is, exploiting the vulnerability of cancer cells, which have lost one mechanism of DNA repair by targeting a second pathway, may be a particularly attractive therapeutic approach.. Targeting the nuclear enzyme PARP-1 represents a new and novel approach to the treatment of EOC and appears to be particularly promising for those carry‐ ing mutations in the BRCA1 and 2 genes. Poly(ADPribose) polymerase (PARP) is an en‐ zyme, which plays an important role in the recognition and repair of single-strand DNA breaks via the base excision repair pathway. Over the last few years it has become apparent that in cells, which have lost BRCA1 or BRCA2, components of a second DNA repair path‐ way, homologous recombination, are particularly sensitive to PARP inhibition. These data suggest that PARP inhibitors may be particularly useful for the treatment of women with hereditary BRCA1/2-associated EOC. Targeted therapy using PARP inhibitors has become an important novel strategy for treating those with hereditary ovarian cancer. Furthermore the identification of other subpopulations of women with EOC who may benefit from this approach is an active area of research. There are currently 17 members of the PARP super‐ family identified. PARP-1 is the most studied enzyme. In the preclinical setting, PARP-1 in‐ hibitors enhance the cytotoxic effects of ionizing radiation and cytotoxic chemotherapy. Additionally, in the preclinical setting, the use of PARP-1 inhibitors as single agents did not cause any measurable toxicity, but the combination of PARP-1 inhibitor with temozolomide in the tumor bearing mice caused significant toxicity. There did not seem to be a correlation,

The degree of risk of ovarian cancer, potential morbidity and mortality of surgery, and the risks associated with early menopause, should be taken into account when consider‐ ing prophylactic oophorectomy for high-risk women. Adverse effects of bilateral oopho‐ rectomy and premature menopause include infertility, vasomotor symptoms, decline in sexual interest and activity, cardiovascular disease, and osteoporosis. Among women who have not taken hormone therapy, women undergoing bilateral oophorecotmy were twice as likely to have moderate or severe hot flashes than women who underwent nat‐ ural menopause (odds ratio [OR] = 2.44; 95% CI, 1.03–5.77). Women at increased heredi‐ tary risk of ovarian cancer who underwent oophorectomy without hormone therapy reported statistically significantly more vasomotor symptoms than women choosing screening or those using hormone replacement therapy (HRT). These women also report‐ ed lower sexual function scores but the difference was not statistically significant. A meta-analysis of early menopause as a risk factor for cardiovascular disease observed a pooled risk of 4.55 (95% CI, 2.56–8.01) among women with bilateral oophorectomy and early menopause (defined as younger than 50 years). Early menopause is also associated with an increased risk of fracture (OR = 1.5; 95% CI, 1.2–1.8).

#### **6. Treatment**

salpingo-oophorectomy between ages 35 to 40 years. However, performing prophylactic sal‐ pingo-oophorectomy before age 45 must be considered in the context of the potential mor‐ bidity of estrogen deprivation at an early age. Oophorectomy before age 45 has been associated with a hazard ratio of 1.96 for death from all causes (p 0.002). However, adminis‐ tration of estrogen replacement eliminated this risk. Many physicians consider estrogen therapy for women without a personal history of breast cancer who undergo prophylactic salpingo-oophorectomy before the age of 45.29 It should be noted that early prophylactic salpingo-oophorectomy is less important for BRCA2 carriers who are known to develop ovarian cancer at approximately the same age as patients with sporadic cancer. Only 1.2% of BRCA2 carriers will have ovarian cancer by the age of 50, so prophylactic salpingo-oopho‐ rectomy may safely be delayed until these patients are closer to menopause. The disadvan‐ tages of prophylactic salpingo-oophorectomy include the fact that it is an invasive surgical intervention, there is loss of ovarian tissue with accompanying hormone deprivation, and it is an irreversible decision. However, in contrast to surveillance and chemoprevention, pro‐ phylactic salpingo-oophorectomy has proven efficacy over an extended time period. Cost analyses comparing surveillance, oral contraceptives, and prophylactic salpingo-oophorec‐ tomy have shown that although any primary prevention strategy was cost effective, prophy‐ lactic salpingo-oophorectomy dominated all other strategies in women with BRCA mutations. Consequently, prophylactic salpingo-oophorectomy is recommended for all BRCA carriers, with timing dependent on the type of BRCA1 or BRCA2 mutation, childbear‐ ing status, and the age of onset of ovarian cancer within the family. The resultant physical and emotional outcomes of repeated gynecological screening or prophylactic oophorectomy must be discussed before and after genetic testing. A study of 315 women with documented HNPCC–associated germline mutations found no ovarian cancer among 47 women who had bilateral salpingo-oophorectomy and 12 cases (5%) among women with mutations who

150 Ovarian Cancer - A Clinical and Translational Update

had not had surgery for a prevented fraction of 100% (95% CI, 62%–100%).

with an increased risk of fracture (OR = 1.5; 95% CI, 1.2–1.8).

The degree of risk of ovarian cancer, potential morbidity and mortality of surgery, and the risks associated with early menopause, should be taken into account when consider‐ ing prophylactic oophorectomy for high-risk women. Adverse effects of bilateral oopho‐ rectomy and premature menopause include infertility, vasomotor symptoms, decline in sexual interest and activity, cardiovascular disease, and osteoporosis. Among women who have not taken hormone therapy, women undergoing bilateral oophorecotmy were twice as likely to have moderate or severe hot flashes than women who underwent nat‐ ural menopause (odds ratio [OR] = 2.44; 95% CI, 1.03–5.77). Women at increased heredi‐ tary risk of ovarian cancer who underwent oophorectomy without hormone therapy reported statistically significantly more vasomotor symptoms than women choosing screening or those using hormone replacement therapy (HRT). These women also report‐ ed lower sexual function scores but the difference was not statistically significant. A meta-analysis of early menopause as a risk factor for cardiovascular disease observed a pooled risk of 4.55 (95% CI, 2.56–8.01) among women with bilateral oophorectomy and early menopause (defined as younger than 50 years). Early menopause is also associated Over the past ten years, the focus of management for BRCA1/2mutation carriers has been on cancer prevention and early cancer detection. However, despite prophylactic measures to reduce risk of EOC, many BRCA1/2 carriers have cancer at the time their mutation is diag‐ nosed and more will develop in the future. The treatment of patients with BRCA associated EOC is so far identical to those with sporadic disease. Data suggested that cancers associat‐ ed with BRCA mutations responded differently to chemotherapy. Tan et al. compared 22 BRCA-positive patients with EOC to 44 nonhereditary EOC controls in a matched case-con‐ trol study. They found that BRCA-positive patients have higher response rates to first line platinum-based treatment (81.8%versus 43.2%, P =.004) as well as to subsequent lines of platinum-based treatments (second line, 91.7% versus 40.9%, P =.004), third line, 100% v 14,3% (P<. 002) and time of first relapse (5v 1.6 years; P<. 001). They conclude that BRCApositive EOC patients have better outcomes than nonhereditary EOC cases. There exists a clinical syndrome of BRCAness that includes serous histology, high response rates to first and subsequent lines of platinum-based treatment, longer tumor free interval between re‐ lapses and improved overall survival [44].

Over recent years the investigation of DNA repair in cancer cells has been a very active area of translational research. All cells have a number of overlapping pathways to protect the ge‐ nome from DNA damage, which occurs as a result of normal cell cycling, environmental in‐ sults, or cytotoxic chemotherapy. It is well recognized that when mutations occur within these DNA repair pathways there is an increased risk of malignant transformation and che‐ motherapy resistance. Much research has focused on protecting cells from DNA damage and/or restoring DNA repair function. However, emerging data suggest that the concept of "synthetic lethality," that is, exploiting the vulnerability of cancer cells, which have lost one mechanism of DNA repair by targeting a second pathway, may be a particularly attractive therapeutic approach.. Targeting the nuclear enzyme PARP-1 represents a new and novel approach to the treatment of EOC and appears to be particularly promising for those carry‐ ing mutations in the BRCA1 and 2 genes. Poly(ADPribose) polymerase (PARP) is an en‐ zyme, which plays an important role in the recognition and repair of single-strand DNA breaks via the base excision repair pathway. Over the last few years it has become apparent that in cells, which have lost BRCA1 or BRCA2, components of a second DNA repair path‐ way, homologous recombination, are particularly sensitive to PARP inhibition. These data suggest that PARP inhibitors may be particularly useful for the treatment of women with hereditary BRCA1/2-associated EOC. Targeted therapy using PARP inhibitors has become an important novel strategy for treating those with hereditary ovarian cancer. Furthermore the identification of other subpopulations of women with EOC who may benefit from this approach is an active area of research. There are currently 17 members of the PARP super‐ family identified. PARP-1 is the most studied enzyme. In the preclinical setting, PARP-1 in‐ hibitors enhance the cytotoxic effects of ionizing radiation and cytotoxic chemotherapy. Additionally, in the preclinical setting, the use of PARP-1 inhibitors as single agents did not cause any measurable toxicity, but the combination of PARP-1 inhibitor with temozolomide in the tumor bearing mice caused significant toxicity. There did not seem to be a correlation,

however, between the antitumor activity and the toxicity of the PARP inhibitor-temozolo‐ mide combinations, suggesting that toxicity and chemosensitization were by different mech‐ anisms. In 2005, two preclinical papers demonstrated the sensitivity of BRCA1- and BRCA2 deficient cell lines to PARP inhibition. The first paper by Bryant et al. demonstrated reduced survival of BRCA2-deficient cell lines with four PARP inhibitors. They concluded that BRCA2- deficient cells were sensitive to PARP inhibition, and that monotherapy with one of these agents could selectively kill cancer cells. In the same year, Farmer et al. demonstrated how both BRCA1- and BRCA2-deficient cells lines were sensitive to inhibition of PARP-1, and that BRCA2 deficient cells were more than 1000 times more sensitive to nanomolar con‐ centrations of PARP inhibitor. Both of these papers demonstrated how homozygotes (tumor cells) are sensitive to the mechanism of PARP inhibition, whereas heterozygotes (the rest of the patient's cells) are insensitive to this mechanism and should not exhibit toxicity. These findings from two independent groups using different chemical classes of PARP inhibitors on different BRCA deficient cell lines were the first to suggest the potent effect of PARP in‐ hibition. A number of PARP inhibitors have entered the clinic in both intravenous and oral formulations. The four, which are furthest along in terms of development, are AGO14699 (Pfizer), AZD2281 (AstraZeneca), ABT-888 (Abbott), and BSI-201 (BI Par), and all four of these compounds demonstrate profound inhibition of PARP-1.Olaparib (AZD2281, KU-0059436, AstraZeneca) is an oral small-molecule PARP inhibitor. Yap et al. presented the first clinical evidence demonstrating the sensitivity of BRCA-mutated cancers to PARP in‐ hibitor monotherapy in a study in 2007. This phase I trial included 44 patients, of which 11 patients had a BRCA mutation associated cancer. Dose escalation was guided by toxicity, pharmacokinetic and pharmacodynamic data. Based on the encouraging antitumor activity, many in whom had BRCA1/2 mutations, the trial was subsequently expanded to concentrate on cancers in patients with BRCA mutations. The drug was well tolerated in both BRCA mutated and normal populations. Most toxicities were grade 1-2 (≥95%), consisting of fati‐ gue (28%), nausea (28%), vomiting (18%), loss of taste (13%), and anorexia (12%). Grade 3-4 toxicities were rare, consisting of myelosuppression (≤5%), nausea and vomiting (2-3%), and dizziness or mood changes (2- 3%) [27]. Of the 60 patients that were enrolled and treated, 19 of 23 BRCA-positive carriers were evaluable. 12 of the 19 (63%) had a clinical benefit from olaparib, with radiologic or tumor marker responses, or stable disease for 4 months or more. Patient response was seen in those receiving a minimum of 100 mg twice daily up to 400 mg twice daily. Response was the greatest in patients with platinum-sensitive disease, although duration of response was the same regardless of the platinum-free interval. Recently data was presented from a phase II study of olaparib in women with advanced EOC with known mutations in BRCA1/2. Two patient cohorts received continuous oral olaparib in 28-day cy‐ cles; 33 patients received 400 mg orally twice daily, while 24 patients received 100 mg twice daily. The choice of dosing and schedule was based on the phase I trial above. The objective response rate measured by RECIST criteria was 33% at the 400 mg dose, and 12.5% at the 100 mg dose, suggesting that there may be a dose response effect. The toxicity profile was mainly mild, consisting of grade 1 or 2 nausea (44%) and fatigue (35%), with few grade 3 or 4 toxicities. Interestingly, although numbers were low, in this study there appeared to be a higher response rate in platinum resistant patients (38% versus 14%), which was opposite to

that observed in the earlier phase I study, where response was the greatest in platinum-sen‐ sitive patients. Laboratory studies have previously suggested that platinum resistant pa‐ tients may reacquire BRCA function thus potentially making them resistant to the effects of PARP inhibition. Taken together, the clinical data suggest that we still have a lot to learn with regard to target populations and the role of PARP inhibition. Furthermore, data from the phase II study appears to give an early indication that response (both RECIST and CA125) may be greater in those patients with BRCA2 mutations. This would be in line with the known mechanism of action of the two BRCA proteins as BRCA2 plays a key role in the repair pathway; whereas BRCA1 functions as a signaling molecule. This phase II study con‐ cluded that oral olaparib is well-tolerated and highly active in advanced, chemotherapy re‐ fractory BRCA-deficient EOC, with greater activity seen at a higher dose of 400 mg twice daily. The optimal patient group with respect to platinum sensitivity has not been defined. Reassuringly in the clinical studies there does not appear to be an increase in toxicity be‐ tween BRCA mutation carriers compared to noncarriers, supporting the theory that PARP inhibitors should not result in increased toxicity to heterozygote cells. These recent phase I and phase II trials are particularly promising for patients with BRCA-associated EOC. Fur‐ ther phase II trials are currently underway which will help further elucidate the role and po‐ tential for this new targeted therapy. Loss of BRCA1/2 function is not exclusive to inheriting a mutation in the BRCA1/2 genes. The results seen in known BRCA1 and 2 mutation carriers may also be relevant to the sporadic EOC patient population. Epigenetic gene inactivation is a well-recognized phenomenon with 31% of EOC exhibiting aberrant methylation of the BRCA1 promoter. Furthermore, genetic or epigenetic events occurring in other components of the HR pathway can be found in sporadic EOC. These tumors seem to be similar to BRCA1- or BRCA2-mutated tumors, even though they do not have mutations to either of these genes, a concept called "BRCAness." One molecular characterization study suggested that over 50% of patients with high-grade EOC had loss of BRCA function, either by genetic or epigenetic events [34]. Studies have shown that the loss of functional proteins in the HR pathway may lead these cells to be sensitive to PARP inhibition. Identification of "BRCAlike" EOC populations who may benefit from this new therapy through the identification and validation of biomarkers is an active area of ongoing research. Several PARP inhibitors are under investigation either as single agents and/or in combination with other agents or treatment modalities. Phase II studies in women with advanced EOC in both BRCA1/2 mu‐ tation carriers and high-grade EOC of unknown BRCA status are ongoing. Currently, ola‐ parib is being evaluated in a randomized phase II trial comparing this agent with pegylated liposomal doxorubicin in patients with BRCA-mutated EOC with a platinum-free interval of 0–12 months. More combination studies in women with both hereditary and sporadic EOC are expected in the future. Further defining the role of PARP inhibitors in the clinic is ongo‐ ing. Olaparib is being evaluated in a randomized placebo-controlled trial as a maintenance therapy in patients with sporadic EOC at high risk of early recurrence. Furthermore, some suggest that PARP inhibitors could be used to prevent cancers in patients who are BRCA mutation carriers. This approach, however, requires careful consideration and some caution with the potential for the development of drug resistance in long-term use of PARP inhibi‐ tors. Investigation of the PARP inhibitors in the nonhereditary EOC population is very ac‐

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 153

that observed in the earlier phase I study, where response was the greatest in platinum-sen‐ sitive patients. Laboratory studies have previously suggested that platinum resistant pa‐ tients may reacquire BRCA function thus potentially making them resistant to the effects of PARP inhibition. Taken together, the clinical data suggest that we still have a lot to learn with regard to target populations and the role of PARP inhibition. Furthermore, data from the phase II study appears to give an early indication that response (both RECIST and CA125) may be greater in those patients with BRCA2 mutations. This would be in line with the known mechanism of action of the two BRCA proteins as BRCA2 plays a key role in the repair pathway; whereas BRCA1 functions as a signaling molecule. This phase II study con‐ cluded that oral olaparib is well-tolerated and highly active in advanced, chemotherapy re‐ fractory BRCA-deficient EOC, with greater activity seen at a higher dose of 400 mg twice daily. The optimal patient group with respect to platinum sensitivity has not been defined. Reassuringly in the clinical studies there does not appear to be an increase in toxicity be‐ tween BRCA mutation carriers compared to noncarriers, supporting the theory that PARP inhibitors should not result in increased toxicity to heterozygote cells. These recent phase I and phase II trials are particularly promising for patients with BRCA-associated EOC. Fur‐ ther phase II trials are currently underway which will help further elucidate the role and po‐ tential for this new targeted therapy. Loss of BRCA1/2 function is not exclusive to inheriting a mutation in the BRCA1/2 genes. The results seen in known BRCA1 and 2 mutation carriers may also be relevant to the sporadic EOC patient population. Epigenetic gene inactivation is a well-recognized phenomenon with 31% of EOC exhibiting aberrant methylation of the BRCA1 promoter. Furthermore, genetic or epigenetic events occurring in other components of the HR pathway can be found in sporadic EOC. These tumors seem to be similar to BRCA1- or BRCA2-mutated tumors, even though they do not have mutations to either of these genes, a concept called "BRCAness." One molecular characterization study suggested that over 50% of patients with high-grade EOC had loss of BRCA function, either by genetic or epigenetic events [34]. Studies have shown that the loss of functional proteins in the HR pathway may lead these cells to be sensitive to PARP inhibition. Identification of "BRCAlike" EOC populations who may benefit from this new therapy through the identification and validation of biomarkers is an active area of ongoing research. Several PARP inhibitors are under investigation either as single agents and/or in combination with other agents or treatment modalities. Phase II studies in women with advanced EOC in both BRCA1/2 mu‐ tation carriers and high-grade EOC of unknown BRCA status are ongoing. Currently, ola‐ parib is being evaluated in a randomized phase II trial comparing this agent with pegylated liposomal doxorubicin in patients with BRCA-mutated EOC with a platinum-free interval of 0–12 months. More combination studies in women with both hereditary and sporadic EOC are expected in the future. Further defining the role of PARP inhibitors in the clinic is ongo‐ ing. Olaparib is being evaluated in a randomized placebo-controlled trial as a maintenance therapy in patients with sporadic EOC at high risk of early recurrence. Furthermore, some suggest that PARP inhibitors could be used to prevent cancers in patients who are BRCA mutation carriers. This approach, however, requires careful consideration and some caution with the potential for the development of drug resistance in long-term use of PARP inhibi‐ tors. Investigation of the PARP inhibitors in the nonhereditary EOC population is very ac‐

however, between the antitumor activity and the toxicity of the PARP inhibitor-temozolo‐ mide combinations, suggesting that toxicity and chemosensitization were by different mech‐ anisms. In 2005, two preclinical papers demonstrated the sensitivity of BRCA1- and BRCA2 deficient cell lines to PARP inhibition. The first paper by Bryant et al. demonstrated reduced survival of BRCA2-deficient cell lines with four PARP inhibitors. They concluded that BRCA2- deficient cells were sensitive to PARP inhibition, and that monotherapy with one of these agents could selectively kill cancer cells. In the same year, Farmer et al. demonstrated how both BRCA1- and BRCA2-deficient cells lines were sensitive to inhibition of PARP-1, and that BRCA2 deficient cells were more than 1000 times more sensitive to nanomolar con‐ centrations of PARP inhibitor. Both of these papers demonstrated how homozygotes (tumor cells) are sensitive to the mechanism of PARP inhibition, whereas heterozygotes (the rest of the patient's cells) are insensitive to this mechanism and should not exhibit toxicity. These findings from two independent groups using different chemical classes of PARP inhibitors on different BRCA deficient cell lines were the first to suggest the potent effect of PARP in‐ hibition. A number of PARP inhibitors have entered the clinic in both intravenous and oral formulations. The four, which are furthest along in terms of development, are AGO14699 (Pfizer), AZD2281 (AstraZeneca), ABT-888 (Abbott), and BSI-201 (BI Par), and all four of these compounds demonstrate profound inhibition of PARP-1.Olaparib (AZD2281, KU-0059436, AstraZeneca) is an oral small-molecule PARP inhibitor. Yap et al. presented the first clinical evidence demonstrating the sensitivity of BRCA-mutated cancers to PARP in‐ hibitor monotherapy in a study in 2007. This phase I trial included 44 patients, of which 11 patients had a BRCA mutation associated cancer. Dose escalation was guided by toxicity, pharmacokinetic and pharmacodynamic data. Based on the encouraging antitumor activity, many in whom had BRCA1/2 mutations, the trial was subsequently expanded to concentrate on cancers in patients with BRCA mutations. The drug was well tolerated in both BRCA mutated and normal populations. Most toxicities were grade 1-2 (≥95%), consisting of fati‐ gue (28%), nausea (28%), vomiting (18%), loss of taste (13%), and anorexia (12%). Grade 3-4 toxicities were rare, consisting of myelosuppression (≤5%), nausea and vomiting (2-3%), and dizziness or mood changes (2- 3%) [27]. Of the 60 patients that were enrolled and treated, 19 of 23 BRCA-positive carriers were evaluable. 12 of the 19 (63%) had a clinical benefit from olaparib, with radiologic or tumor marker responses, or stable disease for 4 months or more. Patient response was seen in those receiving a minimum of 100 mg twice daily up to 400 mg twice daily. Response was the greatest in patients with platinum-sensitive disease, although duration of response was the same regardless of the platinum-free interval. Recently data was presented from a phase II study of olaparib in women with advanced EOC with known mutations in BRCA1/2. Two patient cohorts received continuous oral olaparib in 28-day cy‐ cles; 33 patients received 400 mg orally twice daily, while 24 patients received 100 mg twice daily. The choice of dosing and schedule was based on the phase I trial above. The objective response rate measured by RECIST criteria was 33% at the 400 mg dose, and 12.5% at the 100 mg dose, suggesting that there may be a dose response effect. The toxicity profile was mainly mild, consisting of grade 1 or 2 nausea (44%) and fatigue (35%), with few grade 3 or 4 toxicities. Interestingly, although numbers were low, in this study there appeared to be a higher response rate in platinum resistant patients (38% versus 14%), which was opposite to

152 Ovarian Cancer - A Clinical and Translational Update

tive with both the impact of treatment on patients without BRCA defects and the search for populations of women who have lost functional proteins in the HR pathway. Investigation of PARP inhibitor resistance and ways to overcome this resistance are emerging fields. The emerging data regarding the use of PARP inhibitors in patients with BRCA-associated EOC are encouraging. Identification of further patient groups who will benefit from this ap‐ proach is also indicated. Clinical trials underway will hopefully improve the prognosis of women with Epithelial Ovarian Cancer [45-53].

[3] National Cancer Institute: PDQ® Ovarian Cancer Screening. Bethesda, MD: National Cancer Institute. Date last modified 01/26/2012. Available at:http://cancer.gov/cancer‐

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 155

[4] National Cancer Institute: PDQ® Ovarian Cancer Screening. Bethesda, MD: National Cancer Institute. Date last modified 09/30/2011. Available athttp://cancer.gov/cancer‐

[5] Genetics of Breast and Ovarian Cancer (PDQ) Health Professional Version Last modified 08/08/2012. Available at: http://cancertopics/pdq/genetics/breast-and-ovari‐

[6] American Cancer Society: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online http://www.cancer.gov/global/web/policies/

[7] Landen Jr, CN,Birrer MJ and Sood AK. Early Events in the Pathogenesis of Epithelial

[8] Vaughan S et al. Rethinking ovarian cancer: recommendations for improving out‐

[9] Spellman, et al. Integrated Genomic Analyses of Ovarian Carcinoma. Nature

[10] BRCA1 and BRCA2: Cancer Risk and Genetic Testing. National Cancer Institute.

[11] Dowdy SC and Hartmann LC. Management of Hereditary Ovarian Cancer by Ameri‐

[12] Greene MH, Kohlmann W, Popik WC and Offit K. Cancer Genetics in Practice: Cur‐

[13] Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian can‐

[14] Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005; 23

[15] King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited

[16] Reedy M, Gallion H, Fowler JM, et al. Contribution of BRCA1 and BRCA2 to familial ovarian cancer: A gynecologic oncology group study. Gynecol Oncol 2002; 85

[17] Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-re‐ ducing surgery in common hereditary cancer syndromes. J Clin Oncol 2006; 24

rent Guidelines and Emerging Issues. ASCO Educational Book 2004.

Ovarian Cancer. Doi: 10.1200/JCO.2006.07.9970 JCO 2008; 26(6) 995-100.

topics/pdq/screening/ovarian/HealthProfessional. Accessed 09/16/2012.

topics/pdq/screening/ovarian/Patient version. Accessed 09/16/2012.

an Health Professional. Accessed 09/01/2012.

comes. Nature Reviews Cancer 2011; 11 719-725.

Available on-line. Reviewed: 05/29/2009 accessed 9/22/2012.

mutations in BRCA1 and BRCA2. Science 2003; 302 643-646.

can Society of Clinical Oncology 2007 Educational book.

page 8. Last accessed July 31, 2012.

2011;DOI: 10.1038/nature 10166.

cer. Am J Hum Genet 2001; 68:700-710.

276-292.

255-259.

4642-4660.

#### **7. Conclusions**

Genetic testing can identify women with a hereditary increased risk to develop Ovarian Cancer. This information is extremely useful if the candidate for genetic testing is willing to accept prophylactic surgery. For patients who already have Ovarian Cancer Genetic testing will offer useful information for the relatives but it can also help plan their own treatment. Published data regarding the use of PARP inhibitors in patients with BRCA-associated EOC are encouraging. Studies in combination with chemotherapy are also producing encourag‐ ing results and there are several ongoing studies in patients with hereditary and sporadic cancer as well. These studies will clarify the mechanisms of DNA repair and how this can be exploited to improve treatment results. The development of diagnostic tests in order to se‐ lect patients likely to be sensitive to PARP inhibitors will also be very useful. The combina‐ tion of prevention, early diagnosis and more effective disease management will hopefully improve EOC prognosis in the near future.

#### **Author details**

#### Constantine Gennatas

2nd Department Of Surgery, Areteion Hospital, University of Athens, Athens, Greece

#### **References**

[3] National Cancer Institute: PDQ® Ovarian Cancer Screening. Bethesda, MD: National Cancer Institute. Date last modified 01/26/2012. Available at:http://cancer.gov/cancer‐ topics/pdq/screening/ovarian/HealthProfessional. Accessed 09/16/2012.

tive with both the impact of treatment on patients without BRCA defects and the search for populations of women who have lost functional proteins in the HR pathway. Investigation of PARP inhibitor resistance and ways to overcome this resistance are emerging fields. The emerging data regarding the use of PARP inhibitors in patients with BRCA-associated EOC are encouraging. Identification of further patient groups who will benefit from this ap‐ proach is also indicated. Clinical trials underway will hopefully improve the prognosis of

Genetic testing can identify women with a hereditary increased risk to develop Ovarian Cancer. This information is extremely useful if the candidate for genetic testing is willing to accept prophylactic surgery. For patients who already have Ovarian Cancer Genetic testing will offer useful information for the relatives but it can also help plan their own treatment. Published data regarding the use of PARP inhibitors in patients with BRCA-associated EOC are encouraging. Studies in combination with chemotherapy are also producing encourag‐ ing results and there are several ongoing studies in patients with hereditary and sporadic cancer as well. These studies will clarify the mechanisms of DNA repair and how this can be exploited to improve treatment results. The development of diagnostic tests in order to se‐ lect patients likely to be sensitive to PARP inhibitors will also be very useful. The combina‐ tion of prevention, early diagnosis and more effective disease management will hopefully

2nd Department Of Surgery, Areteion Hospital, University of Athens, Athens, Greece

[1] National Cancer Institute: PDQ® Ovarian Epithelial Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified 06/22/2012. Available at: http:// cancer.gov/cancertopics/pdq/treatment/ovarianepithelial /Health Professional. Ac‐

[2] National Cancer Institute: PDQ® Ovarian Cancer Prevention. Bethesda, MD: Nation‐ al Cancer Institute. Date last modified 02/06/2012. Available at: http://cancer.gov/ cancertopics/pdq/prevention/ovarian/HealthProfessional. Accessed 08/08/2012.

women with Epithelial Ovarian Cancer [45-53].

154 Ovarian Cancer - A Clinical and Translational Update

improve EOC prognosis in the near future.

**7. Conclusions**

**Author details**

**References**

Constantine Gennatas

cessed 09/16/2012.

[18] NIH Consensus Conference. Ovarian cancer: Screening, treatment, and follow-up: NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995; 273 491-497.

[32] Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation.

The Genetics of Ovarian Cancer http://dx.doi.org/10.5772/54541 157

[33] Colgan TJ, Murphy J, Cole DE, et al. Occult carcinoma in prophylactic oophorectomy specimens: Prevalence and association with BRCA germline mutation status. Am J

[34] Lu KH, Garber JE, Cramer DW, et al. Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy. J Clin Oncol 2000; 18

[35] Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk

[36] Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers

[37] Tobacman JK, Greene MH, Tucker MA, et al. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 1982; 2 (8302)

[38] Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylac‐ tic oophorectomy in women with a family history of ovarian cancer. A report of the

[39] Casey MJ, Synder C, Bewtra C, et al. Intra-abdominal carcinomatosis after prophylac‐ tic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecol Oncol 2005; 97 (2) 457-67.

[40] Madalinska JB, van Beurden M, Bleiker EM, et al. The impact of hormone replace‐ ment therapy on menopausal symptoms in younger high-risk women after prophy‐

[41] Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of

[42] Offit K, Kauff ND: Reducing the risk of gynecologic cancer in the Lynch syndrome. N Engl J Med 2006; 354 (3) 293-5. syndrome. N Engl J Med 2006;354 (3) 261-9.

[43] Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers

[44] Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, Ardern-Jones A, Norman A, Kaye SB, Gore ME. "BRCAness" syndrome in ovarian cancer: a case-con‐ trol study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008; 1;

lactic salpingo-oophorectomy. J Clin Oncol 2006; 24 (22) 3576-82. 47.

of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346 (21)1616-22.

Gilda Radner Familial Ovarian Cancer Registry. Cancer 1993; 71 (9) 2751-5.

of ovarian cancer. A prospective study. JAMA 1993; 270 (23) 2813-8.

of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346 (21) 1616-22.

JAMA 2006; 296 185-192.

2728-2732.

795-7.

Surg Pathol 2001; 25 1283-1289.

gynecologic cancers in the Lynch

26(34):5530-6. Epub 2008 Oct 27.

[32] Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 2006; 296 185-192.

[18] NIH Consensus Conference. Ovarian cancer: Screening, treatment, and follow-up: NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995; 273 491-497.

[19] National Comprehensive Cancer Network. Hereditary breast and/or ovarian cancer: NCCN Practice Guidelines in Oncology - v. 1.2006. National Comprehensive Cancer

[20] Buys SS, Partridge E, Greene MH, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial

[21] Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian can‐

[22] Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimo‐ dal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian

[23] Kobayashi H, Yamada Y, Sado T, et al. A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer 2008; 18 (3) 414-20.

[24] Einhorn N, Bast R, Knapp R, et al. Long-term follow-up of the Stockholm screening

[25] Vasen HF, Tesfay E, Boonstra H, et al. Early detection of breast and ovarian cancer in

[26] Olivier RI, Lubsen-Brandsma MA, Verhoef S, et al. CA125 and transvaginal ultra‐ sound monitoring in high-risk women cannot prevent the diagnosis of advanced

[27] Buys SS, Partridge E, Black A, et al.: Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized

[28] Zhang Z, Bast RC Jr, Yu Y, et al.: Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 2004; 64 (16)

[29] Petricoin EF, Ardekani AM, Hitt BA, et al.: Use of proteomic patterns in serum to

[30] Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carrier

[31] Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346 1609-1615.

21 of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346 1616-1622.

screen of a randomized trial. Am J Obstet Gynecol 2005;193 (5) 1630-9.

cer screening in a randomized trial. Obstet Gynecol 2009; 113 (4) 775-82.

Cancer Screening (UKCTOCS). Lancet Oncol 2009; 10 (4) 327-40.

study on ovarian cancer. Gynecol Oncol 2000; 79 (3) 466-70.

ovarian cancer. Gynecol Oncol 2006; 100 (1) 20-6.

Controlled Trial. JAMA2011; 305 (22) 2295-303.

identify ovarian cancer. Lancet 2002; 359 (9306): 572-7.

5882-90.

families with BRCA mutations. Eur J Cancer 2005; 41 (4): 549-54.

Network, 2006.

156 Ovarian Cancer - A Clinical and Translational Update

[45] Roux R. Zwifel M,Gordon JS and Rustin GJS. Biologicals in the Up front Treatment of Ovarian Cancer: Focus on Bevacizumab and Poly(ADP-Ribose) Polymerase Inhibi‐ tors. Journal of Oncology 2010; Article ID 151750, 6 pages doi:10.1155/2010/151750

**Section 3**

**Ovarian Cancer Therapeutics**

**Ovarian Cancer Therapeutics**

[45] Roux R. Zwifel M,Gordon JS and Rustin GJS. Biologicals in the Up front Treatment of Ovarian Cancer: Focus on Bevacizumab and Poly(ADP-Ribose) Polymerase Inhibi‐ tors. Journal of Oncology 2010; Article ID 151750, 6 pages doi:10.1155/2010/151750

[46] Gien LT and Mackay HJ. Review Article The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer. Journal of Oncology 2010; Article ID

[47] Huehls AM, Wagner JM, Huntoon CJ, Karnitz LM. Identification of DNA Repair Pathways that Affect the Survival of Ovarian Cancer Cells Treated with a PARP In‐ hibitor in a Novel Drug Combination. Mol Pharmacol 2012; July 25. [Epub ahead of

[48] Marchetti C, Imperiale L, Gasparri ML, Palaia I, Pignata S, Boni T, Bellati F, Benedetti Panici P. Olaparib, PARP1 inhibitor in ovarian cancer.Expert Opin Investig Drugs

[49] Maxwell KN, Domchek SM. Cancer treatment according to BRCA1 and BRCA2 mu‐ tations.Nat Rev Clin Oncol 2012; 14;9(9):520-8. doi: 10.1038/nrclinonc.2012.123. Epub

[50] Marchetti C, Imperiale L, Gasparri ML, Palaia I, Pignata S, Boni T, Bellati F, Benedetti Panici P. Olaparib, PARP1 inhibitor in ovarian cancer.Expert Opin Investig Drugs 2012; 21(10) 1575-84. Epub 2012 Jul 13.PMID22788971Ratner ES, Sartorelli AC, Lin ZP Poly (ADP-ribose) polymerase inhibitors: on the horizon of tailored and personalized therapies for epithelial ovarian cancer. Curr Opin Oncol 2012; 24(5) 564-71. PMID:

[51] Westin SN, Herzog TJ, Coleman RL. Investigational agents in development for the treatment of ovarian cancer.Invest New Drugs 2012; June 4. [Epub ahead of print]

[52] Shigetomi H, Higashiura Y, Kajihara H, Kobayashi H.Targeted molecular therapies for ovarian cancer: an update and future perspectives (Review).Oncol Rep 2012; 28(2)

[53] Tinker AV, Gelmon K. The Role of PARP Inhibitors in the Treatment of Ovarian Car‐

395-408. doi: 10.3892/or.2012.1833. Epub 2012 May 25.PMID: 22641286

cinomas. Curr Pharm Des. 2012;18 (25):3770-4. PMID: 22591423

151750, 6 pages doi:10.1155/2010/151750

158 Ovarian Cancer - A Clinical and Translational Update

2012 Jul 24.PMID: 22825375

2012; 21(10):1575-84. Epub 2012 Jul 13.PMID:22788971

print]

22759740.

PMID: 22661305.

**Chapter 8**

**Surgical Treatment of Ovarian Cancer**

Javier Valero de Bernabé and Ivan Diaz-Padilla

Despite great efforts in developing novel screening, diagnosis and therapeutic strategies, the incidence and mortality of ovarian cancer have not significantly changed in the last 30 years. [1] It remains the leading cause of death from gynecologic malignancy with a lifetime proba‐ bility of developing the disease of 1 in 59.[1] Worldwide, approximately 200.000 women are annually diagnosed with ovarian cancer,[2] and almost 70% of them will be diagnosed at ad‐ vanced stage disease.[3] With current treatment modalities, the 5-year survival rate ranges from 80–95% for those with organ-confined or early stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage I-II); to 30 – 40% for those women with advanced dis‐ ease, FIGO stage III-IV. Thus, ovarian cancer is a challenging and complex malignancy.[4]

Surgical management of ovarian cancer remains as the cornerstone treatment of this disease. [5] An adequate full surgical staging in women with early stage disease has demonstrated to improve oncologic outcome.[6] On the other hand, complete surgical cytoreduction is the only modifiable prognosis factor for patients with advanced disease. This chapter will de‐ scribe the rationale and surgical steps for an adequate surgical staging for women with early stage ovarian cancer, and for obtaining the maximal surgical cytoreduction in women affect‐

Approximately 25% of newly diagnosed ovarian cancer will be early stage disease. Progno‐ sis is good with survival rates ranging from 80 % to 95 % when recommended treatment is

and reproduction in any medium, provided the original work is properly cited.

© 2013 Minig et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

**2. Surgical treatment of early stage epithelial ovarian cancer**

Additional information is available at the end of the chapter

Lucas Minig, M. Guadalupe Patrono,

ed by advanced stage and relapsed disease.

Rafael Alvarez Gallego,

http://dx.doi.org/10.5772/53972

**1. Introduction**

### **Surgical Treatment of Ovarian Cancer**

Lucas Minig, M. Guadalupe Patrono, Rafael Alvarez Gallego, Javier Valero de Bernabé and Ivan Diaz-Padilla

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53972

#### **1. Introduction**

Despite great efforts in developing novel screening, diagnosis and therapeutic strategies, the incidence and mortality of ovarian cancer have not significantly changed in the last 30 years. [1] It remains the leading cause of death from gynecologic malignancy with a lifetime proba‐ bility of developing the disease of 1 in 59.[1] Worldwide, approximately 200.000 women are annually diagnosed with ovarian cancer,[2] and almost 70% of them will be diagnosed at ad‐ vanced stage disease.[3] With current treatment modalities, the 5-year survival rate ranges from 80–95% for those with organ-confined or early stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage I-II); to 30 – 40% for those women with advanced dis‐ ease, FIGO stage III-IV. Thus, ovarian cancer is a challenging and complex malignancy.[4]

Surgical management of ovarian cancer remains as the cornerstone treatment of this disease. [5] An adequate full surgical staging in women with early stage disease has demonstrated to improve oncologic outcome.[6] On the other hand, complete surgical cytoreduction is the only modifiable prognosis factor for patients with advanced disease. This chapter will de‐ scribe the rationale and surgical steps for an adequate surgical staging for women with early stage ovarian cancer, and for obtaining the maximal surgical cytoreduction in women affect‐ ed by advanced stage and relapsed disease.

#### **2. Surgical treatment of early stage epithelial ovarian cancer**

Approximately 25% of newly diagnosed ovarian cancer will be early stage disease. Progno‐ sis is good with survival rates ranging from 80 % to 95 % when recommended treatment is

© 2013 Minig et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

followed.[5] These patients are initially managed by comprehensive surgical staging, which is relevant not only for identifying women with truly early stage disease, but also to select patients who will be candidates for adjuvant chemotherapy.

Peritoneal washing from paracolic gutters, pelvis and abdominal cavity should be done in the absence of ascites. It is estimated that over 30% of patients with stage I disease have tu‐ moral cells on cytological examination.[11] Careful inspection and palpation is preformed to detect extra-ovarian implants in a systematic way: starting by right paracolic space, advanc‐ ing the hand to the right kidney, suprahepatic space, the right diaphragm, right hepatic lobe, gallbladder, Morrison´s pouch, left hemi-diaphragm, left hepatic lobe, spleen, stomach, transverse colon, left kidney and left paracolic space. The lesser sac is entered on the left side of the gastrocolic ligament. Both surfaces of the mesentery should be examined and retro‐ peritoneal vascular areas should be palpated as well. The result of this comprehensive pro‐

Surgical Treatment of Ovarian Cancer http://dx.doi.org/10.5772/53972 163

The ovaries need to be examined for capsule rupture or external excrescences. The affected ovary must then be removed for frozen section. Although the influence on the prognosis of the intraoperative rupture of malignant ovarian tumors is controversial,[12] adnexal masses should be removed intact. If malignancy is confirmed in the frozen section, full surgical staging, as previously described, must be performed by the extension of the incision up to xifoid appendix. Contralateral oophorectomy and total hysterectomy is completed due to

Even though controversial, random peritoneal biopsies are indicated in early-stage disease. A retrospective study demonstrated that less than 4% of patients with ovarian cancer were upstaged due to positive peritoneal biopsies. No patient, however, had a change in treat‐ ment recommendations based on these biopsies.[13] Infracolic omentectomy should be per‐ formed from the hepatic to splenic flexure. During dissection, the lesser sac is developed dissecting the posterior and anterior layer of the transverse mesocolon, while preserving the middle colic artery. The omentum is removed and the pedicles are sequentially sutured –

The incidence of lymph-node involvement in patients with disease confined to the ovary is 5% in only pelvic nodes, 9% in aortic nodes and 6% in both pelvic and aortic nodes.[14] Sys‐ tematic lymphadenectomy as part of surgical staging of apparent early stage ovarian cancer is associated with a statistically significant increase in median operative time, median blood loss, and the proportion of patients undergoing blood transfusions.[15] Systematic lympha‐ denectomy, however, significantly improves progression-free survival (PFS) rates, without a statistically significant impact on overall survival (OS). [14, 15] Lymphatic drainage of the ovaries is known to follow the gonadal blood supply that reaches the renal vein, on the left side, and the inferior vena cava, on the right side. Pelvic lymphadenectomy should include removal of nodes from paravesical and pararectal spaces, including bilateral common iliac

nodes. Aortic nodes should be removed from aortic bifurcation to the renal veins.[14]

ligated. Appendectomy is only reserved for mucinous histology.

**5. Retropetitoneal lymph node dissection**

cedure should be properly described.

the possibility of synchronous cancer.

#### **3. Rationale for surgical staging**

Adequate surgical staging procedures include: exploration of abdomen/pelvis, peritoneal washings, bilateral salpingo-oophorectomy, hysterectomy, peritoneal biopsies of Cul-de-sac, pelvic walls, paracolic gutters, diaphragm, suspicious areas, omentectomy, appendectomy, as well as pelvic and para-aortic node dissection up to the renal veins. (TABLE 1)[7],[8] These procedures are needed to find hidden disease in nearly 18% of women[8], which has implications in the prognosis and subsequent patient treatment.[9] Surgeon expertise is cru‐ cial given that it was correlated with under-staged ovarian cancer. Several studies demon‐ strated that over 30% of patients operated by general gynecologists or general surgeons were upstaged by gynecologist oncologists by finding disease on pelvic-aortic lymph nodes, diaphragm biopsies and omentum.[6, 10] Moreover, as it has been demonstrated, inade‐ quate initial surgical staging leads to a higher risk of developing recurrent disease despite receiving adjuvant chemotherapy.[6] Thus, if the operative risk is not too high, all patients should be routinely re-staged before starting chemotherapy.

**Table 1.** Surgical staging procedures for early stage ovarian cancer

#### **4. Surgical staging procedures**

Midline vertical incision is the recommended surgical approach for initial management of suspected early stage ovarian cancer. The incision is firstly made from the pubis to the um‐ bilicus and then progressed to xifoid appendix, if surgical staging is indicated following the frozen section diagnosis. The abdominal-pelvic cavity is opened and visualized. If free fluid is present, a minimum sample of 100 cc[3] should be obtained for cytological examination.

<sup>•</sup> Peritoneal cytology/ascites drainage

<sup>•</sup> Careful and systematic abdominal exploration – inspect and palpate all peritoneal surface

Peritoneal washing from paracolic gutters, pelvis and abdominal cavity should be done in the absence of ascites. It is estimated that over 30% of patients with stage I disease have tu‐ moral cells on cytological examination.[11] Careful inspection and palpation is preformed to detect extra-ovarian implants in a systematic way: starting by right paracolic space, advanc‐ ing the hand to the right kidney, suprahepatic space, the right diaphragm, right hepatic lobe, gallbladder, Morrison´s pouch, left hemi-diaphragm, left hepatic lobe, spleen, stomach, transverse colon, left kidney and left paracolic space. The lesser sac is entered on the left side of the gastrocolic ligament. Both surfaces of the mesentery should be examined and retro‐ peritoneal vascular areas should be palpated as well. The result of this comprehensive pro‐ cedure should be properly described.

The ovaries need to be examined for capsule rupture or external excrescences. The affected ovary must then be removed for frozen section. Although the influence on the prognosis of the intraoperative rupture of malignant ovarian tumors is controversial,[12] adnexal masses should be removed intact. If malignancy is confirmed in the frozen section, full surgical staging, as previously described, must be performed by the extension of the incision up to xifoid appendix. Contralateral oophorectomy and total hysterectomy is completed due to the possibility of synchronous cancer.

Even though controversial, random peritoneal biopsies are indicated in early-stage disease. A retrospective study demonstrated that less than 4% of patients with ovarian cancer were upstaged due to positive peritoneal biopsies. No patient, however, had a change in treat‐ ment recommendations based on these biopsies.[13] Infracolic omentectomy should be per‐ formed from the hepatic to splenic flexure. During dissection, the lesser sac is developed dissecting the posterior and anterior layer of the transverse mesocolon, while preserving the middle colic artery. The omentum is removed and the pedicles are sequentially sutured – ligated. Appendectomy is only reserved for mucinous histology.

#### **5. Retropetitoneal lymph node dissection**

followed.[5] These patients are initially managed by comprehensive surgical staging, which is relevant not only for identifying women with truly early stage disease, but also to select

Adequate surgical staging procedures include: exploration of abdomen/pelvis, peritoneal washings, bilateral salpingo-oophorectomy, hysterectomy, peritoneal biopsies of Cul-de-sac, pelvic walls, paracolic gutters, diaphragm, suspicious areas, omentectomy, appendectomy, as well as pelvic and para-aortic node dissection up to the renal veins. (TABLE 1)[7],[8] These procedures are needed to find hidden disease in nearly 18% of women[8], which has implications in the prognosis and subsequent patient treatment.[9] Surgeon expertise is cru‐ cial given that it was correlated with under-staged ovarian cancer. Several studies demon‐ strated that over 30% of patients operated by general gynecologists or general surgeons were upstaged by gynecologist oncologists by finding disease on pelvic-aortic lymph nodes, diaphragm biopsies and omentum.[6, 10] Moreover, as it has been demonstrated, inade‐ quate initial surgical staging leads to a higher risk of developing recurrent disease despite receiving adjuvant chemotherapy.[6] Thus, if the operative risk is not too high, all patients

patients who will be candidates for adjuvant chemotherapy.

should be routinely re-staged before starting chemotherapy.

• Total abdominal hysterectomy and bilateral salpingo-oophorectomy

• Biopsy or scrapings from the undersurface of both diaphragms

**Table 1.** Surgical staging procedures for early stage ovarian cancer

• Careful and systematic abdominal exploration – inspect and palpate all peritoneal surface

• Random and directed peritoneal biopsies – posterior cul-de-sac, bladder reflection, both pelvic sidewalls and both

Midline vertical incision is the recommended surgical approach for initial management of suspected early stage ovarian cancer. The incision is firstly made from the pubis to the um‐ bilicus and then progressed to xifoid appendix, if surgical staging is indicated following the frozen section diagnosis. The abdominal-pelvic cavity is opened and visualized. If free fluid is present, a minimum sample of 100 cc[3] should be obtained for cytological examination.

**3. Rationale for surgical staging**

162 Ovarian Cancer - A Clinical and Translational Update

• Peritoneal cytology/ascites drainage

• Pelvic and aortic lymphadenectomy

• Appendectomy (for mucinous histology)

**4. Surgical staging procedures**

• Infracolicomentectomy

paracolic spaces

The incidence of lymph-node involvement in patients with disease confined to the ovary is 5% in only pelvic nodes, 9% in aortic nodes and 6% in both pelvic and aortic nodes.[14] Sys‐ tematic lymphadenectomy as part of surgical staging of apparent early stage ovarian cancer is associated with a statistically significant increase in median operative time, median blood loss, and the proportion of patients undergoing blood transfusions.[15] Systematic lympha‐ denectomy, however, significantly improves progression-free survival (PFS) rates, without a statistically significant impact on overall survival (OS). [14, 15] Lymphatic drainage of the ovaries is known to follow the gonadal blood supply that reaches the renal vein, on the left side, and the inferior vena cava, on the right side. Pelvic lymphadenectomy should include removal of nodes from paravesical and pararectal spaces, including bilateral common iliac nodes. Aortic nodes should be removed from aortic bifurcation to the renal veins.[14]

#### **6. Minimally invasive surgery for surgical staging ovarian cancer**

Over the last years, laparoscopy has gained an important role for the management of suspect‐ ed adnexal masses. High-volume centers have reported their experience in performing a com‐ prehensive surgical staging by using minimally invasive surgery.[16],[17] Nezhat et al. [16] reported a case series of 36 patients with early stage invasive ovarian carcinoma managed by laparoscopy. They showed 100% OS rate with a mean duration of follow-up of 55.9 months. Chi et al. [17] conducted a case control study by staging 20 patients with early ovarian cancer with laparoscopy compared with 30 patients staged with laparotomy. There were no differen‐ ces in the omental specimen size or number of lymph nodes removed. Blood loss and hospital stay were lower for the laparoscopy group, with longer operating time. There were no conver‐ sions to laparotomy or other intraoperative complications in the laparoscopy group.

worldwide recommendation consists of primary maximal surgical cytoreduction followed

served for selected patients and it includes surgical cytoreduction in between chemotherapy courses, usually after three or four cycles. This strategy is called neoadjuvant chemotherapy followed by interval debulking surgery. (fig 1) The appropriate selection of patients for each

Prognostic factors in women with advanced stage EOC was described in literature based on

three prospective randomized phase III multicenter trials, which enrolled 3388 patients with advanced EOC between 1995 and 2002. Univariate and multivariate analysis revealed nonmodifiable significant prognostic factors for OS and PFS such as: age, performance status (ECOG 2 versus 0-1), FIGO stage (IIIC-IV versus IIB-IIIB), subtype histology (Mucinous ver‐ sus serous), histology grade (grade 2-3 versus 1), presence of large volume ascites (> 500 mL). The only significant modifiable prognosis factor was postoperative residual tumor (0

23] did a combined exploratory analysis of

5,7] An alternative strategy is re‐

Surgical Treatment of Ovarian Cancer http://dx.doi.org/10.5772/53972 165

by 6 cycles of intravenous carboplatin plus paclitaxel. [

modality of treatment will be described below.

**Figure 1.** Treatment options for advanced stage ovarian cancer

retrospective data.[22] Recently, Du Buois et al., [

**8. Prognostic factors**

Despite laparoscopic staging of early ovarian cancer seems to be a safe and feasible proce‐ dure performed by expert surgeons, the possibility of cyst rupture or port-site metastases re‐ main controversial. The immediate effect of tumor rupture is that a patient with a potentially curable disease will require additional adjuvant chemotherapy. Preoperative evaluation is essential, as well as the surgical experience and the quality of laparoscopic in‐ struments.[18] Even though there are no specific recommendations, adnexal masses up to 5-6 cm could be reasonably managed by laparoscopy.

The etiology of port-site metastases is uncertain. Several hypotheses include tumor cell en‐ trapment, direct spread from the trocar in which instruments are exchanged, and the ''chim‐ ney effect,'' which suggests that tumor cells travel along the sheath of the trocars with the leaking gas. Port-site metastases have been reported in 1% to 2% of patients with ovarian cancer. However, <5% of port metastases are clinically detected and these sites are likely to respond to chemotherapy.[9]

Robotic surgery has emerged as an innovative minimally invasive approach in the field of gynecology. The da Vinci Surgical System (Intuitive Surgical, Inc, Sunnyvale, California, USA) offers several advantages over conventional laparoscopy including three-dimensional view, greater dexterity, and tremor filtration. Most of the data regarding the application of robotic technology for ovarian cancer staging are included in the literature used in the as‐ sessment for its implementation in other gynecologic malignancies, such as cervical and en‐ dometrial cancer.[19] Data are still scarce but promising.

#### **7. Treatment of advanced stage disease: Surgical cytoreduction**

Advanced-stage disease means that the disease is extended to pelvic/ aortic lymph nodes, peritoneum, intra-abdominal organs or disease outside the abdominal cavity.[20] In 1975, a landmark study quantified residual disease and demonstrated for the first time an inverse relationship between residual tumor and oncologic outcome. [ 21] The goal of surgery is to resect as much tumor as possible obtaining, ideally, a complete resection. The standard worldwide recommendation consists of primary maximal surgical cytoreduction followed by 6 cycles of intravenous carboplatin plus paclitaxel. [ 5,7] An alternative strategy is re‐ served for selected patients and it includes surgical cytoreduction in between chemotherapy courses, usually after three or four cycles. This strategy is called neoadjuvant chemotherapy followed by interval debulking surgery. (fig 1) The appropriate selection of patients for each modality of treatment will be described below.

**Figure 1.** Treatment options for advanced stage ovarian cancer

#### **8. Prognostic factors**

**6. Minimally invasive surgery for surgical staging ovarian cancer**

sions to laparotomy or other intraoperative complications in the laparoscopy group.

5-6 cm could be reasonably managed by laparoscopy.

dometrial cancer.[19] Data are still scarce but promising.

relationship between residual tumor and oncologic outcome. [

respond to chemotherapy.[9]

164 Ovarian Cancer - A Clinical and Translational Update

Despite laparoscopic staging of early ovarian cancer seems to be a safe and feasible proce‐ dure performed by expert surgeons, the possibility of cyst rupture or port-site metastases re‐ main controversial. The immediate effect of tumor rupture is that a patient with a potentially curable disease will require additional adjuvant chemotherapy. Preoperative evaluation is essential, as well as the surgical experience and the quality of laparoscopic in‐ struments.[18] Even though there are no specific recommendations, adnexal masses up to

The etiology of port-site metastases is uncertain. Several hypotheses include tumor cell en‐ trapment, direct spread from the trocar in which instruments are exchanged, and the ''chim‐ ney effect,'' which suggests that tumor cells travel along the sheath of the trocars with the leaking gas. Port-site metastases have been reported in 1% to 2% of patients with ovarian cancer. However, <5% of port metastases are clinically detected and these sites are likely to

Robotic surgery has emerged as an innovative minimally invasive approach in the field of gynecology. The da Vinci Surgical System (Intuitive Surgical, Inc, Sunnyvale, California, USA) offers several advantages over conventional laparoscopy including three-dimensional view, greater dexterity, and tremor filtration. Most of the data regarding the application of robotic technology for ovarian cancer staging are included in the literature used in the as‐ sessment for its implementation in other gynecologic malignancies, such as cervical and en‐

Advanced-stage disease means that the disease is extended to pelvic/ aortic lymph nodes, peritoneum, intra-abdominal organs or disease outside the abdominal cavity.[20] In 1975, a landmark study quantified residual disease and demonstrated for the first time an inverse

resect as much tumor as possible obtaining, ideally, a complete resection. The standard

21] The goal of surgery is to

**7. Treatment of advanced stage disease: Surgical cytoreduction**

Over the last years, laparoscopy has gained an important role for the management of suspect‐ ed adnexal masses. High-volume centers have reported their experience in performing a com‐ prehensive surgical staging by using minimally invasive surgery.[16],[17] Nezhat et al. [16] reported a case series of 36 patients with early stage invasive ovarian carcinoma managed by laparoscopy. They showed 100% OS rate with a mean duration of follow-up of 55.9 months. Chi et al. [17] conducted a case control study by staging 20 patients with early ovarian cancer with laparoscopy compared with 30 patients staged with laparotomy. There were no differen‐ ces in the omental specimen size or number of lymph nodes removed. Blood loss and hospital stay were lower for the laparoscopy group, with longer operating time. There were no conver‐

> Prognostic factors in women with advanced stage EOC was described in literature based on retrospective data.[22] Recently, Du Buois et al., [ 23] did a combined exploratory analysis of three prospective randomized phase III multicenter trials, which enrolled 3388 patients with advanced EOC between 1995 and 2002. Univariate and multivariate analysis revealed nonmodifiable significant prognostic factors for OS and PFS such as: age, performance status (ECOG 2 versus 0-1), FIGO stage (IIIC-IV versus IIB-IIIB), subtype histology (Mucinous ver‐ sus serous), histology grade (grade 2-3 versus 1), presence of large volume ascites (> 500 mL). The only significant modifiable prognosis factor was postoperative residual tumor (0

ovarian cancer

versus >1 mm). (Table 2) This study highlighted the importance of an adequate surgical management of women affected by ovarian cancer as the key-point for improving oncologic outcomes given that the quality of surgical cytoreduction was the only modifiable prognosis factor for survival.