02 BONE DENSIT1Y AND CARDIOVASCULAR RISK FACTOR CHANGES IN POSTMIENOPAUSAL WOMEN TREATED WITII TAMOXIFEN.
IMMUNCYTOCHEMICAL DETECTION OF TUMOR CELLS IN BONE MORROW IN PATIENTS WITH PRIMARY BREAST CANCER. Diel, I., Kaufmann, M., Krempien, B., Kaul, S., Gorner, R., Costa-, S., Bastert, G. Dept. of Gyn. and Obst. University of Heidelberg, F.R.G. About 95 % of patients who present with breast cancer have local disease only on staging by conventional methods. Nevertheless more than 40 % of these patients relapse within five years. To improve the predictive value for recurrency we examined the bone morrow of 128 patients with primary breast cancer and compared with other prognostic factors. Bone morrow aspirates from 2 - 6 sites of the skeleton were taken (iliac crest + sternum) as well as biopsies for histological examination. The immunhistochemical studies were carried out on interphase smears and stained with cytokeratin antibodies (PKK ) and antibodies against tumor-specific antigen TAG 12 (12H12). All patients were screened for distant metastasis (X-ray, ultrasound, bone scan). Tumor cells and micrometastases in bone morrow were detected in 24 %. Their presence was related to other prognostic factors (tumorsize), vascular invasion, estrogen/progesterone receptors. The median duration of follow up was 24 month.14 Pat. (50%)of the tumor cell positive group relapsed versus only 4 patients in the tumor cell free group. In 30 % we found bone metastases. The relapse free interval was significantly shorter for patients with micrometastases. The presence of tumor cells in bone morrow aspirates detected at the time of primary surgery is a useful prognostic factor and a good predictor of bone metastasis and may help in selecting patients for systemic adjuvant treatment.
Love. R.R., Mazess, R.B., Wiebe, D.A., and DeMets, D.L.
University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53706, USA. We conducted a two-year, double-blind, placebo-controlled biological and symptom toxicity trial of tamoxifen 10 mg p.o. BID in 140 clinically postmenopausal women under age 65 with a history of axillary node-negative breast cancer. Subjects were evaluated at a baseline visit, and at 3, 6, 12, 18 and 24 months at which times comprehensive symptom and health behavior questionnaires were completed, physical examinations were made, serum and plasma samples obtained and bone mineral density (BMD) measurements were made at the lumbar spine (dual protein absorptiometry) and radius shaft (single photon absorptiometry). Beginning at the 3 month visit and through 18 months tamoxifen-treated subjects developed a decrease in total plasma cholesterol (-30 mg/dL; p=0.0001 at 18 months) due to a decrease in derived LDL cholesterol (-30 mg/dL; p=0.0001 at 18 months). At 18 months there were no statistically significant changes in HDL cholesterol or triglycerides. At one year there were no significant treatment group differences in systolic blood pressure, diastolic blood pressure or weight. At 6 months, Fibrinogen levels fell in tamoxifen-treated subjects (-48 mg/dL; p=0.0003). Through 18 months the slope of BMD change in the lumbar spine shows decrease in the placebo group and an increase in the tamoxifentreated women (-1.27%; +032% changes in BMID per year for each group respectively; p=0.0002). The slope of the BMD change at the radius shaft shows a trend for a smaller decrease in tatmoxifen-treated subjects (-1.44%, -0.73%; p=0.13).
We conclude that tamoxifen has favorable effects on cardiovascular risk factors and preserves BMD in postmenopausal women with a history of breast cancer.
04
03
DOES TAMOXIFEN HAVE A DIRECT EFFECT ON THE BREAST? RELEVANCE TO PROPHYLACTIC THERAPY.
FEASIBILITY OF TAMOXIFEN IN CHEMOPREVENTION OF BREAST CANCER.
NO(RitAL HULHAN
Walker, K J, Price-Thomas, M*, Candlish, W+ and Nicholson, R I Tenovus Institute for Cancer Research, University of Wales College of Medicine, Heath Park, Cardiff, U.K.* Royal Gwent Newport, U.K. +Dept of Pathology Royal Infirmary, Glasgow, U.K.
A Jones,TJ Powles,S Ashley,C Tillyer,J Treleaven
Depts of Medicine, Computing, Biochemistry, Haematology,Royal Marsden Hospital, Sutton & London.
Immunohistochemical assays have been used to determine the expression of the oestrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor (EGFR) in normal breast tissue (n=42) and to relate these to an index of cell proliferation by Ki67 immunostaining. Cancer associated normal tissue was also obtained from patients receiving 40 mg of tamoxifen daily (n=18).
The importance of biologically active oestrogen in the aetiology of breast cancer can be inferred from epidemiological data and has been established experimentally in laboratory animals. A panel of relative risk factors can define a subpopulation of women at high risk of breast cancer. We are investigating the use of tamoxifen 20mg daily for chemoprevention of breast cancer in a prospective double-blind placebo controlled trial. Over 400 women have been accrued in a pilot feasibility study. Compliance is greater than 80% for both groups at one year and there are no differences in acute toxicity (nausea, headaches,amenorrhoea or vasomotor The fibrinogen/anti-thrombin Ill ratios were disturbance). unaffected and there was a significant reduction in total cholesterol (0.85mmol/l: p19fnol )
adjuvant arm (AT)
25% (56/222)
39%
therapeutic arm (PRT)
44% (94/213)
47% (68/146)
34% ( 150/435 )
43% ( 131/307 )
TOTAL
"Overview".
ER POOR (O or < 2cfmol)
(63/161)
3
These results vary as expected (ER rich better than ER poor and, in each ER subgroup, AT better than PRT). Considering only the 281 relapsed cases (all should have had either AT or PRT) the median DFI is prolonged by AT in BOTH ER subgroups. However, this gain is reflected in total survival only in the ER poor. In the ER rich, the gain in survival from PRT given to controlarm cases more than compensates for their shorter DFI. Thus one could argue that T should be reserved for the therapy of first relapse in the ER rich and used as adjuvant therapy only for the ER poor! Valid?
13
045
046 BREAST CANCER CELLS KINETIC: A PROGNOSTIC PARAMETER IN PERIOPERATIVE ADJUVANT CHEMOTHERAPY
BREAST CARCINOMA AMONG ASIANS LIVING IN LEICESTER, ENGLAND
Davidson N G P, Barret B, Bircumshaw D, and Khanna S Department of Radiotherapy and Oncology, Leicester Royal Infirmary, Leicester, England
P.Pronzato. A.Alama, A.Rubagotti, D.Amoroso, G.Bertelli,
P.F.Conte, M.R.Sertoli, R.Rosso National Institute for Cancer Research, Genova - Italy
A retrospective study was performed to study the natural history of breast cancer amoung Asians living in Leicester. Sixty three Asian patients with breast carcinoma seen at the Leicester Royal Infirmary Radiotherapy Department from January 1977 until December 1988 were identified by name from the departmental cancer registry.
Thymidine Labeling Index (TLI) is a tumor kinetic parameter which has been shown to correlate with prognosis of primary breast cancer patients (pts): however, its relationship with response to adjuvant chemotherapy (CT) in terms of relapse freee survival (RFS) and overall survival (OS) is not yet fully understood. We are therefore evaluating TLI in pts recruited in a prospective randomized study of perioperative adjuvant chemotherapy (pCT), in which stage I pts are randomized to 1 cycle of pCT or no adjuvant therapy, while stage II pts are randomized to I cycle of pCT followed by 11 cycles of postoperative CT versus 12 cycles of postoperative CT and no pCT. pCT consists of Cyclophosphamide 600 mg/sm, Epidoxorubicin 60 mg/sm and 5-Fluorouracil 600 mg/sm i.v. on day 1 every 3 weeks. So far TLI value and its correlation with RFS have been evaluated in 155 pts. Median TLI in this series is 0.7: overall, no significant difference in relapse incidence, after a median followup of 36 months, can be observed between pts with high TLI (aO.7) and low TLI ( 1.00 fingerprint changes
Oncology Unit, Guy's Hospital, London SE1 9RT 1976 and 1985, 391 pts (202 premenopausal, 189
postmenopausal) with node positive breast cancer were randomised after mastectomy and axillary clearance to receive CMF (n=193) or no adjuvant therapy (n=198). Details and early results have previously been reported (Lancet 1984 ii, 307311). Median follow-up is now 8 years. For premenopausal pts, both relapse free survival (RFS) and survival (S) were significantly prolonged in patients receiving CMF (RFS, p 4 nodes (p=0.001), with ER -ve (p=0.002) and ER +ve (p=0.004) tumours, and with PgR -ve (p=O.O1) and PgR +ve (p 40 years was not influenced by the development of amenorrhoea. It was not possible to assess the influence of the development of amenorrhoea on RFS for premenopausal pts aged >40 years, as only 2 out of 60 continued to menstruate. However, premenopausal pts aged 41-54 benefitted significantly from CMF (p
IMMUNCYTOCHEMICAL DETECTION OF TUMOR CELLS IN BONE MORROW IN PATIENTS WITH PRIMARY BREAST CANCER. Diel, I., Kaufmann, M., Krempien, B., Kaul, S., Gorner, R., Costa-, S., Bastert, G. Dept. of Gyn. and Obst. University of Heidelberg, F.R.G. About 95 % of patients who present with breast cancer have local disease only on staging by conventional methods. Nevertheless more than 40 % of these patients relapse within five years. To improve the predictive value for recurrency we examined the bone morrow of 128 patients with primary breast cancer and compared with other prognostic factors. Bone morrow aspirates from 2 - 6 sites of the skeleton were taken (iliac crest + sternum) as well as biopsies for histological examination. The immunhistochemical studies were carried out on interphase smears and stained with cytokeratin antibodies (PKK ) and antibodies against tumor-specific antigen TAG 12 (12H12). All patients were screened for distant metastasis (X-ray, ultrasound, bone scan). Tumor cells and micrometastases in bone morrow were detected in 24 %. Their presence was related to other prognostic factors (tumorsize), vascular invasion, estrogen/progesterone receptors. The median duration of follow up was 24 month.14 Pat. (50%)of the tumor cell positive group relapsed versus only 4 patients in the tumor cell free group. In 30 % we found bone metastases. The relapse free interval was significantly shorter for patients with micrometastases. The presence of tumor cells in bone morrow aspirates detected at the time of primary surgery is a useful prognostic factor and a good predictor of bone metastasis and may help in selecting patients for systemic adjuvant treatment.
Love. R.R., Mazess, R.B., Wiebe, D.A., and DeMets, D.L.
University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53706, USA. We conducted a two-year, double-blind, placebo-controlled biological and symptom toxicity trial of tamoxifen 10 mg p.o. BID in 140 clinically postmenopausal women under age 65 with a history of axillary node-negative breast cancer. Subjects were evaluated at a baseline visit, and at 3, 6, 12, 18 and 24 months at which times comprehensive symptom and health behavior questionnaires were completed, physical examinations were made, serum and plasma samples obtained and bone mineral density (BMD) measurements were made at the lumbar spine (dual protein absorptiometry) and radius shaft (single photon absorptiometry). Beginning at the 3 month visit and through 18 months tamoxifen-treated subjects developed a decrease in total plasma cholesterol (-30 mg/dL; p=0.0001 at 18 months) due to a decrease in derived LDL cholesterol (-30 mg/dL; p=0.0001 at 18 months). At 18 months there were no statistically significant changes in HDL cholesterol or triglycerides. At one year there were no significant treatment group differences in systolic blood pressure, diastolic blood pressure or weight. At 6 months, Fibrinogen levels fell in tamoxifen-treated subjects (-48 mg/dL; p=0.0003). Through 18 months the slope of BMD change in the lumbar spine shows decrease in the placebo group and an increase in the tamoxifentreated women (-1.27%; +032% changes in BMID per year for each group respectively; p=0.0002). The slope of the BMD change at the radius shaft shows a trend for a smaller decrease in tatmoxifen-treated subjects (-1.44%, -0.73%; p=0.13).
We conclude that tamoxifen has favorable effects on cardiovascular risk factors and preserves BMD in postmenopausal women with a history of breast cancer.
04
03
DOES TAMOXIFEN HAVE A DIRECT EFFECT ON THE BREAST? RELEVANCE TO PROPHYLACTIC THERAPY.
FEASIBILITY OF TAMOXIFEN IN CHEMOPREVENTION OF BREAST CANCER.
NO(RitAL HULHAN
Walker, K J, Price-Thomas, M*, Candlish, W+ and Nicholson, R I Tenovus Institute for Cancer Research, University of Wales College of Medicine, Heath Park, Cardiff, U.K.* Royal Gwent Newport, U.K. +Dept of Pathology Royal Infirmary, Glasgow, U.K.
A Jones,TJ Powles,S Ashley,C Tillyer,J Treleaven
Depts of Medicine, Computing, Biochemistry, Haematology,Royal Marsden Hospital, Sutton & London.
Immunohistochemical assays have been used to determine the expression of the oestrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor (EGFR) in normal breast tissue (n=42) and to relate these to an index of cell proliferation by Ki67 immunostaining. Cancer associated normal tissue was also obtained from patients receiving 40 mg of tamoxifen daily (n=18).
The importance of biologically active oestrogen in the aetiology of breast cancer can be inferred from epidemiological data and has been established experimentally in laboratory animals. A panel of relative risk factors can define a subpopulation of women at high risk of breast cancer. We are investigating the use of tamoxifen 20mg daily for chemoprevention of breast cancer in a prospective double-blind placebo controlled trial. Over 400 women have been accrued in a pilot feasibility study. Compliance is greater than 80% for both groups at one year and there are no differences in acute toxicity (nausea, headaches,amenorrhoea or vasomotor The fibrinogen/anti-thrombin Ill ratios were disturbance). unaffected and there was a significant reduction in total cholesterol (0.85mmol/l: p19fnol )
adjuvant arm (AT)
25% (56/222)
39%
therapeutic arm (PRT)
44% (94/213)
47% (68/146)
34% ( 150/435 )
43% ( 131/307 )
TOTAL
"Overview".
ER POOR (O or < 2cfmol)
(63/161)
3
These results vary as expected (ER rich better than ER poor and, in each ER subgroup, AT better than PRT). Considering only the 281 relapsed cases (all should have had either AT or PRT) the median DFI is prolonged by AT in BOTH ER subgroups. However, this gain is reflected in total survival only in the ER poor. In the ER rich, the gain in survival from PRT given to controlarm cases more than compensates for their shorter DFI. Thus one could argue that T should be reserved for the therapy of first relapse in the ER rich and used as adjuvant therapy only for the ER poor! Valid?
13
045
046 BREAST CANCER CELLS KINETIC: A PROGNOSTIC PARAMETER IN PERIOPERATIVE ADJUVANT CHEMOTHERAPY
BREAST CARCINOMA AMONG ASIANS LIVING IN LEICESTER, ENGLAND
Davidson N G P, Barret B, Bircumshaw D, and Khanna S Department of Radiotherapy and Oncology, Leicester Royal Infirmary, Leicester, England
P.Pronzato. A.Alama, A.Rubagotti, D.Amoroso, G.Bertelli,
P.F.Conte, M.R.Sertoli, R.Rosso National Institute for Cancer Research, Genova - Italy
A retrospective study was performed to study the natural history of breast cancer amoung Asians living in Leicester. Sixty three Asian patients with breast carcinoma seen at the Leicester Royal Infirmary Radiotherapy Department from January 1977 until December 1988 were identified by name from the departmental cancer registry.
Thymidine Labeling Index (TLI) is a tumor kinetic parameter which has been shown to correlate with prognosis of primary breast cancer patients (pts): however, its relationship with response to adjuvant chemotherapy (CT) in terms of relapse freee survival (RFS) and overall survival (OS) is not yet fully understood. We are therefore evaluating TLI in pts recruited in a prospective randomized study of perioperative adjuvant chemotherapy (pCT), in which stage I pts are randomized to 1 cycle of pCT or no adjuvant therapy, while stage II pts are randomized to I cycle of pCT followed by 11 cycles of postoperative CT versus 12 cycles of postoperative CT and no pCT. pCT consists of Cyclophosphamide 600 mg/sm, Epidoxorubicin 60 mg/sm and 5-Fluorouracil 600 mg/sm i.v. on day 1 every 3 weeks. So far TLI value and its correlation with RFS have been evaluated in 155 pts. Median TLI in this series is 0.7: overall, no significant difference in relapse incidence, after a median followup of 36 months, can be observed between pts with high TLI (aO.7) and low TLI ( 1.00 fingerprint changes
Oncology Unit, Guy's Hospital, London SE1 9RT 1976 and 1985, 391 pts (202 premenopausal, 189
postmenopausal) with node positive breast cancer were randomised after mastectomy and axillary clearance to receive CMF (n=193) or no adjuvant therapy (n=198). Details and early results have previously been reported (Lancet 1984 ii, 307311). Median follow-up is now 8 years. For premenopausal pts, both relapse free survival (RFS) and survival (S) were significantly prolonged in patients receiving CMF (RFS, p 4 nodes (p=0.001), with ER -ve (p=0.002) and ER +ve (p=0.004) tumours, and with PgR -ve (p=O.O1) and PgR +ve (p 40 years was not influenced by the development of amenorrhoea. It was not possible to assess the influence of the development of amenorrhoea on RFS for premenopausal pts aged >40 years, as only 2 out of 60 continued to menstruate. However, premenopausal pts aged 41-54 benefitted significantly from CMF (p
