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Second and third generation aromatase inhibitors in the treatment and chemoprevention of breast cancer
10
MONDAY,
In our series the incidence of complications is much lower than those reported in other observations. We are convinced about significance and efficacy of sentinel lymph node identification but our experience in domain is reduced. The therapy of node-negative cases is still subject of controversy. It may be solved by making use of other categories of prognostic factors. We think that our practice, performed in not very modern conditions, is comparable with the same domain in other centers. The results reported by the authoritative institutiions seem to be reproductible in common practice. The treatment for breast cancer is no longer a simple surgical procedure. It is a multidisciplinary problem. The gynecologist is an important member of the team.
0N1.04.02 TAMOXIFEN M.
AND ITS GYNAECOLOGICAL CONSEQUENCES Universitats-Frauenklinik, Frankfurt, Germany
The partial estrogenic activity of tamoxifen leads to a stimulation of the endometrium with consequent development of pre-cancerous hyperplasias and endometrial carcinomas. The relative risk for users compared to non-users has been determined between 2 and 4. However, these cancers are usually detected in early stages and do not have a detrimental outcome. The NSABP - P 1 prevention trial showed that this risk is confined only to postmenopausal women. Vaginal ultrasound scan was recommended previously for early detection of endometrial changes. Due to a tamoxifen-induced edema of the subendometrial stroma, endometrial thickening is often detected, but only atrophic endometrial tissue can be collected by D & C. By this routine ultrasound scan monitoring during tamoxifen treatment has lead to an unjustified high number of unnecessary diagnostic invasive procedures. Patients become clinically symptomatic in most cases by vaginal bleeding similar to non-tamoxifen induced endometrial cancer patients. Currently no endometrial screening is therefore recommended during tamoxifen treatment. However, in the case of vaginal bleeding in postmenopausal women careful diagnosis investigations are essential including endometrial tissue sampling.
0N1.04.04 SECOND AND THIRD GENERATION AROMATASE INHIBITORS IN THE TREATMENT AND CHEMOPREVENTION OF BREAST CANCER. J. UZ Sint Rafael KULeuven, 33 Kapucynenvoer, 3000 Leuven, Belgium Each new generation of aromatase inhibitors has offered improved characteristics compared with previous ones, third generation aromatase inhibitors offering increased potency, specificity and better tolerability than the former compounds. Based on the results of randomized phase III trials, third-generation aromatase inhibitors (anastrozole, letrozole and exemestane ), have displaced progestins as preferred therapy for the treatment of hormoneresponsive metastatic breast cancer patients failing prior tamoxifen treatment. Compared with megestrol acetate, these agents offer improved tolerability and similar or improved objective response rates and quality of life. Moreover, results seem to indicate a potential for improved survival, an outcome most consistently demonstrated by the exemestane data, offering statistically significant improvements in Time to Progression, Time to Treatment Failure and Overall Survival for the exemestane treated patient group. During less than 12 months of followup, exemestane reduced the risk of death by 23% compared to megestrol acetate. Based on these encouraging results, research is currently underway or being planned to assess the role of these third-generation agents as first-line therapy, adjuvant therapy, and for the chemoprevention of breast cancer. Despite their similarities, there are differences among the third-generation aromatase inhibitors. These agents are more correctly categorized as aromatase inhibitors (anastrozole, letrozole) or aromatase inactivators (exemestane) based on differences in their cellular mechanism of action. Whereas aromatase inhibitors produce a reversible inhibition of the aromatase enzyme, aromatase inactivators irreversibly inactivate aromatase. These differences may have important implications in determining optimal endocrine therapy for women with breast cancer, issues that can be addressed only after more information is
gathered on detailed pharmacologic and pharmacokinetic among these agents at the tumor level
SEPTEMBER
differences
RM1.02.01 IN VITRO MATURATION OF OOCYTES. Anne Herlev Hospital, Herlev, Denmark Many attempts have been made to perform in vitro fertilization (IVF) in the natural cycle without the use of exogenous gonadotropins. The combination of immature oocyte retrieval and in vitro maturation (IVM) may enhance the success of natural IVF. Although it is possible to mature and fertilize human oocytes in vitro the success rate in terms of live off spring after IVM has in general been low. There are several possible explanations for the poor developmental capacity of these oocytes. One explanation might be suboptimal culture conditions during maturation in vitro, another might be that the oocytes themselves were defective due to inadequate cytoplasmic maturation. While some studies have focused on improving culture media and optimizing the time interval for maturation before insemination, others have tried to optimize the quality of the oocyte. Suggestions based on own and other data on normal, regular menstruating women: (1) Early priming with oestradiol gave a lower maturation rate and impaired embryonic development compared to late priming with oestradiol. (2) FSH priming did not have any effect on cleavage rate and embryo development. (3) Shortening the maturation period from 48 to 36 and to 30 hours did not compromise the subsequent embryonic development Timing of aspiration enhanced the pregnancy rate (clinical pregnancy rate per aspiration improved from 13% to 23%). Immature oocyte retrieval combined with IVM may in the future be an attractive alternative to conventional IVF. Besides the clinical effects of lowering side effects, especially elimination of hyperstimulation syndrome, this treatment may reduce the costs of IVF. Women that participate in IVM are not exposed to additional discomfort or risks than normally encountered with IVF treatment.
RM1.02.02 CRYOPRESERVATION OF EGGS & EMBRYOS D. L. Healy, Monash Medical Centre, Clayton, Australia Cryopreservation of embryos, oocytes and ovarian tissue represents a high priority in major programs of IVF and assisted reproductive technologies. Protocols for human embryo development, cryopreservation and thawing are now established in many IVF centres with stble results. Wherever possible, patients should have treatment aimed at cryo preserving their embryos. This is clearly the most effective way for them to have a baby in the future. Cryopreservation of human embryos has now been successfully extended to cryopreservation of human blastocysts. By contrast, there is currently no method which gives good survival of human oocytes. Very few ongoing pregnancies or live births have been achieved. It appears to reflect differences in cell volume, membrane permeability, membrane composition, tolerance to cryoproctetants and other as yet unrecognised factors. Rapid cooling and vitrification protocols have also proved effective in the mouse but have yet to be adapted to human oocytes. A male partner is not required. The ovarian tissue can be collected by laparoscopy at anytime of the cycle from patients of any age. No hormonal treatments may be required as the graft itself may support the processes leading to ovulation. Disadvantages of ovarian tissue storage arise because the ovary can serve as a reservoir for infection and disease. In a mouse model, we have demonstrated that frozen - thawed ovarian tissue from mice with lymphoma transmitted lymphoma into grafted control mice. Ovarian tissue storage for oncology patients should be undertaken in large IVF/ART programs, with ethical approval and known protocols with attention to appropriate counselling and dignity for these particularly vulnerable young women.
G
MONDAY,
In our series the incidence of complications is much lower than those reported in other observations. We are convinced about significance and efficacy of sentinel lymph node identification but our experience in domain is reduced. The therapy of node-negative cases is still subject of controversy. It may be solved by making use of other categories of prognostic factors. We think that our practice, performed in not very modern conditions, is comparable with the same domain in other centers. The results reported by the authoritative institutiions seem to be reproductible in common practice. The treatment for breast cancer is no longer a simple surgical procedure. It is a multidisciplinary problem. The gynecologist is an important member of the team.
0N1.04.02 TAMOXIFEN M.
AND ITS GYNAECOLOGICAL CONSEQUENCES Universitats-Frauenklinik, Frankfurt, Germany
The partial estrogenic activity of tamoxifen leads to a stimulation of the endometrium with consequent development of pre-cancerous hyperplasias and endometrial carcinomas. The relative risk for users compared to non-users has been determined between 2 and 4. However, these cancers are usually detected in early stages and do not have a detrimental outcome. The NSABP - P 1 prevention trial showed that this risk is confined only to postmenopausal women. Vaginal ultrasound scan was recommended previously for early detection of endometrial changes. Due to a tamoxifen-induced edema of the subendometrial stroma, endometrial thickening is often detected, but only atrophic endometrial tissue can be collected by D & C. By this routine ultrasound scan monitoring during tamoxifen treatment has lead to an unjustified high number of unnecessary diagnostic invasive procedures. Patients become clinically symptomatic in most cases by vaginal bleeding similar to non-tamoxifen induced endometrial cancer patients. Currently no endometrial screening is therefore recommended during tamoxifen treatment. However, in the case of vaginal bleeding in postmenopausal women careful diagnosis investigations are essential including endometrial tissue sampling.
0N1.04.04 SECOND AND THIRD GENERATION AROMATASE INHIBITORS IN THE TREATMENT AND CHEMOPREVENTION OF BREAST CANCER. J. UZ Sint Rafael KULeuven, 33 Kapucynenvoer, 3000 Leuven, Belgium Each new generation of aromatase inhibitors has offered improved characteristics compared with previous ones, third generation aromatase inhibitors offering increased potency, specificity and better tolerability than the former compounds. Based on the results of randomized phase III trials, third-generation aromatase inhibitors (anastrozole, letrozole and exemestane ), have displaced progestins as preferred therapy for the treatment of hormoneresponsive metastatic breast cancer patients failing prior tamoxifen treatment. Compared with megestrol acetate, these agents offer improved tolerability and similar or improved objective response rates and quality of life. Moreover, results seem to indicate a potential for improved survival, an outcome most consistently demonstrated by the exemestane data, offering statistically significant improvements in Time to Progression, Time to Treatment Failure and Overall Survival for the exemestane treated patient group. During less than 12 months of followup, exemestane reduced the risk of death by 23% compared to megestrol acetate. Based on these encouraging results, research is currently underway or being planned to assess the role of these third-generation agents as first-line therapy, adjuvant therapy, and for the chemoprevention of breast cancer. Despite their similarities, there are differences among the third-generation aromatase inhibitors. These agents are more correctly categorized as aromatase inhibitors (anastrozole, letrozole) or aromatase inactivators (exemestane) based on differences in their cellular mechanism of action. Whereas aromatase inhibitors produce a reversible inhibition of the aromatase enzyme, aromatase inactivators irreversibly inactivate aromatase. These differences may have important implications in determining optimal endocrine therapy for women with breast cancer, issues that can be addressed only after more information is
gathered on detailed pharmacologic and pharmacokinetic among these agents at the tumor level
SEPTEMBER
differences
RM1.02.01 IN VITRO MATURATION OF OOCYTES. Anne Herlev Hospital, Herlev, Denmark Many attempts have been made to perform in vitro fertilization (IVF) in the natural cycle without the use of exogenous gonadotropins. The combination of immature oocyte retrieval and in vitro maturation (IVM) may enhance the success of natural IVF. Although it is possible to mature and fertilize human oocytes in vitro the success rate in terms of live off spring after IVM has in general been low. There are several possible explanations for the poor developmental capacity of these oocytes. One explanation might be suboptimal culture conditions during maturation in vitro, another might be that the oocytes themselves were defective due to inadequate cytoplasmic maturation. While some studies have focused on improving culture media and optimizing the time interval for maturation before insemination, others have tried to optimize the quality of the oocyte. Suggestions based on own and other data on normal, regular menstruating women: (1) Early priming with oestradiol gave a lower maturation rate and impaired embryonic development compared to late priming with oestradiol. (2) FSH priming did not have any effect on cleavage rate and embryo development. (3) Shortening the maturation period from 48 to 36 and to 30 hours did not compromise the subsequent embryonic development Timing of aspiration enhanced the pregnancy rate (clinical pregnancy rate per aspiration improved from 13% to 23%). Immature oocyte retrieval combined with IVM may in the future be an attractive alternative to conventional IVF. Besides the clinical effects of lowering side effects, especially elimination of hyperstimulation syndrome, this treatment may reduce the costs of IVF. Women that participate in IVM are not exposed to additional discomfort or risks than normally encountered with IVF treatment.
RM1.02.02 CRYOPRESERVATION OF EGGS & EMBRYOS D. L. Healy, Monash Medical Centre, Clayton, Australia Cryopreservation of embryos, oocytes and ovarian tissue represents a high priority in major programs of IVF and assisted reproductive technologies. Protocols for human embryo development, cryopreservation and thawing are now established in many IVF centres with stble results. Wherever possible, patients should have treatment aimed at cryo preserving their embryos. This is clearly the most effective way for them to have a baby in the future. Cryopreservation of human embryos has now been successfully extended to cryopreservation of human blastocysts. By contrast, there is currently no method which gives good survival of human oocytes. Very few ongoing pregnancies or live births have been achieved. It appears to reflect differences in cell volume, membrane permeability, membrane composition, tolerance to cryoproctetants and other as yet unrecognised factors. Rapid cooling and vitrification protocols have also proved effective in the mouse but have yet to be adapted to human oocytes. A male partner is not required. The ovarian tissue can be collected by laparoscopy at anytime of the cycle from patients of any age. No hormonal treatments may be required as the graft itself may support the processes leading to ovulation. Disadvantages of ovarian tissue storage arise because the ovary can serve as a reservoir for infection and disease. In a mouse model, we have demonstrated that frozen - thawed ovarian tissue from mice with lymphoma transmitted lymphoma into grafted control mice. Ovarian tissue storage for oncology patients should be undertaken in large IVF/ART programs, with ethical approval and known protocols with attention to appropriate counselling and dignity for these particularly vulnerable young women.
G