- Email: [email protected]
Oestrone-3-methylphosphonothioate (E1MPT) is a potent inhibitor of oestrone sulphatase activity in MCF-7 human breast cancer cells
Abstracts analysis is based on 336 patients (168 on AC and 168 on placebo) available for follow-up. The treatment groups were balanced for all factors (age. T. N stage). At a median follow-up of 8.1 years there was no overall benetit for AG either in terms of event-free or overall survival. There were I05 events (63%) in patients on AG and 107 (64%) in patients on placebo (p=O.41) and 93 deaths (55%) for AG and placebo (p=O.98). Examination of log hazard ratio plots shows that these results are not inconsistent with the significantly improved survival in earlier analyses. There was a marginal advantage in eventfree survival for oestogen receptor positive patients (n = 74: p = 0.0541. There was no difference in sites of relapse. There was a 62 signiticant increase in toxicity for patients receiving AG with respect to lethargy, ataxia and skin rash. Three patients on AG developed a grdnulocytosl\. The lack of survival benetit with long term follow-up may indicate that ammatase inhibitors have less impact on early breast cancer than tarnoxlfen and may imply different mechanisms of action. This could have therapeutic implications for adjuvant therapy.
60 QUANTITATION OF AROMATASE CYTOCHROME P450 mRNA LEVELS IN HUMAN BREAST TUMOURS, USING A COMPARATIVE PCR TECHNIQUE Aitken, J. I*, Hardy, S.C.2, Parbhoo, S.P.2, Cooke, B.A. 1, Simpson, E.tZ.3 Departments of Biochemistry’ & Surgery*, Royal Free Hospital Medical School, Pond Street, London, NW3, UK. Department of Obstetrics & Gynaecology3, University of Texas Southwestern Medical Center, Da//as, Texas, USA Aromatase cytochrome P450 is the final enzyme in the pathway from C I9 androgens to C I8 oestrogens. Approximately I /3 of human breast cancers are oestrogen sensitive. We have previously shown. using the aroma&e tritiated water release assay, that 30% of breast turnour have detectable levels of aromatase activity and hence. the capacity to synthesise oestrogens. As the aromatase assay may not be sensitive enough to detect low levels of the enzyme in small amount!, of tissue, a comparative PCR technique was employed to measure mRNA. levels encoding aromatase in tumour tissue from 12 patients. Rat aromatase cRNA was coamplified as an internal standard to compare amplitication reactions. More patients were shown to be positive for aromatase mRNA (9/l?) compared to aromatase activity (7/121. However, there was no correlation between level. of mesrage and enzyme activity (S=-28. z=- I .c)l:P > 0.05 ). The ability to use the PCR technique to demonstrate expression of aromatase mRNA v+ould also lend itself to assaying material from needle biopsy specimens, thus allowing more appropriate selection of patients for treatment with aromatase inhibitors.
61 THE ROLE OF INTERLEUKIN-6 IN REGULATING BREAST TISSUE AROMATASE ACTIVITY
I6 I
using an explant culture system. Production of IL-6 by tumour tissue (232 + 226 rig/g.. mean *SD.. n = 6) was significantly higher (p
COMBlNAT[ON
OF
THE
AROMATASE
INHIBITORS 4HYDROXYANDROSTENEDIONE (40HA) AND AMINOGLUTHETHIMIDE (AG): AN APPROACH TO MAXIMIZATION OF AROMATASE INHIBITION AND E2 SUPPRESSION? MacNeill F, Dowsett M, Jacobs S, l Lonning P, Pow/es TJ Royal Marsden Hospital, London and Sutton, UK *Haukeland Sykehus, N-5021 Bergen, Norway Aromatase inhibitor is a clinically effective treatment for postmenopausal women with advanced breast cancer. It is not known if there is a direct relationship between aromataqc inhibition. E2 An early limited pilot study suppreaion and clinical response. suggested that sequential combination of 3OHA and AG, aromatase inhibitors with different modes of action, resulted in additional E? suppression with corresponding further climcal responses. This current study was performed to explore further the existence of any link between E7 suppression and additional aromatase inhibition. Ten postmenopausal women with advanced breast cancer received 4OHA 500mg irn weekly for a minimum of S-6 week\ after which AG IOOOmg daily was added. In-vivo istotope aromalase measurement studies were performed pre-treatment. on 40HA and on 40HA/AG combined. Regular plasma samples were taken for endocrine analysis (oestradiol E2). Mean % aromatase inhibition and E? suppression for 40HA 5OOmg im weekly was 91.1% (SEM + 2.5 1and 71.4% (SEM ? 4. I ) respectively. For combined therapy it wa\ Y2.X’I tSEM* 2.3) and 78.1% (SEM + 3.4) respectively. There was no \tati\tically signiiicant difference for either aromatase inhibition or E2 suppression between single and combination therapy. Although in keeping with the previous pilot study a difference between 40HA ‘tnd IOHA/AG E7 suppression of 26.4% (SEM + 7.5) was noted even though aromatase inhibition was unchanged. As expected aromatabe inhibition and E2 suppression by 4OHA are comparable to the prototype inhibitor AG. Combining the two drugs does not produce any statistically detectable difference. The increase in E? suppreahion measured on combination therapy whilst not statistically significant reHect\ _I real trend and i\ consequent upon AG stimulating oestrogen liver metabolism. The lack of correlation between E2 suppression and aromatase inhibition noted in the past has been confirmed in this study. There is no advantage in using a combination of AG/4OHA.
63 OESTRONE-3METHYLPHOSPHONOTHIOATE (ElMPT ) IS Reed, M J, Coldham, NG and Ghilchik M W Unit of Metabolic Medicine and The Breast Clinic, St. Mary’s A POTENT INHIBITOR OF OESTRONE Hospital Medical School, London, UK SULPHATASE ACTIVITY IN MCF-7 HUMAN BREAST CANCER CELLS The aromatase enzyme complex, which converts androstenedione to oestrone. is present in normal and malignant breast tissues and it is possible that factors produced by breast tumours increase aromatase activity in tissues adjacent to the tumour. To investigate such a possibility. the ability of conditioned medium (CM) from cultured tumour derived libroblasts or breast tumour cytosol (BTC) to stimulate aromatase activity in breast cancer cells was examined. Both CM and BTC were found to significantly stimulate aromatase activity and interleukin-6 (IL-6) has now been identified as a factor present in CM from tumour derived fibroblasts which stimulates aromatase activity. The production of IL-6 by breast tumour and normal breast tissues. obtained from patients undergoing mastectomy. has been examined
A. Purohit, L.J. Duncan and M.J. Reed Unit of Metabolic Medicine, St Mary’s Hospital School & Imperial College, London, UK
Medical
Oestrone sulphate stimulates the growth of breast tumours via conversion to oestrone and oestradiol as shown by data from a variety of in vitro and in vivo studies. Oestrone sulphatase. the enzyme which converts oestrone sulphate into oestrone, i\ consistently found in primary mammary carcinoma. This oestrone sulphatase pathway may, therefore. be significant and perhaps the primary means of local produc-
162
The Breast
tion of oestrone in breast tissues. We have synthesized EIMPT, a steroidal competitive inhibitor of oestrone sulphatase activity. In intact MCF-7 breast cancer cells in culture, ElMPT inhibited oestrone sulphatase activity in a dose-dependent mamter. The sulphatase activity in the absence of ElMPT was 89.4 +I- 5.2, 23.5 +I-3.0 and 3.6 +I- 0.2 fmol/2Oh006 cells respectively. Using 1OuM ElMPT, 96% inhibition of oestrone sulphatase activity was achieved. In contrast, Danazol, reported to inhibit the sulphatase, only inhibited oestrone sulphatase by 40% when tested at the same concentration. Furthermore, ElMPI was resistant to metabolism to oestrone in the presence of liver or placental microsomes. The development of inhibitors of oestrone sulphatase represents a novel therapeutic strategy to oestrogen-dependent breast cancer.
64 SHOULD THE AXILLA BE DISSECTED IN SCREEN DETECTED BREAST CANCER? J Walls, CRM Boggis, M Wilson, DL Asbury, JV Roberts, NJ Bundred, RE Manse1 Department of Surgery and Radiology, University Hospital of South Manchester, UK
including 6 (60%) achieving CR. Median initial tumour diameter was 6cm (range 5-9cm). Marked histological down-grading has been seen on serial biopsy with most patients showing only residual scar tissue and scattered isolated malignant cells. Primary medical chemotherapy for large operable breast cancer is effective in preventing mastectomy in the large majority of patients. Early results with infusional CT are encouraging and indicate the need for randomised comparison with conventional CT, it is possible that infusional CT may entirely replace surgery for some patients. This approach also offers a useful “test-bed” for promising new regimens prior to use as adjuvant therapy.
66 TAMOXIFEN AND CASTRATION IN ADDITION TO CYTOTOXICS IN THE TREATMENT OF PREMENOPAUSAL PATIENTS WITH METASTATIC BREAST CANCER. A phase Ill trial of CAF + castration vs CAF + castration + Tamoxifen Rose C, Andersson M, Mouridsen H T, Mailer K Aa, Overgaard M, Larsen PM, Dombernowsky P, Bastholt L, Christensen I, on behalf of the DBCG, Denmark Department of Oncology, Odense University Hospiral, Denmark
The management of axillary nodes in screen detected breast cancer is controversial. Optimal treatment should combine accurate node status with the avoidance of unnecessary morbidity. The aim of this study was to determine if full axillary dissection can be avoided in some women with screen detected cancer. Since October, 1988, 223 breast cancers have been discovered via the screening programme. 180 were invasive, of which 22% were found to be lymph node positive. The presence of involved nodes was associated with large tumour size (p < O.OOS), high grade (p < O.Ol), and the absence of tumour microcalcification (p < 0.05). (see table below; microcalcification data not shown) Pathological tumour size
3 cm
Grade of tumour
Number of involved axillae by grade
one 16 25 4 4
one 0 1 0 2
two 11 46 15 12
three 3 11 7 6
two 0 10 6 6
The efficacy of combined endocrine therapy with ovarian irradiation (Ovx) and Tamoxifen (T) in addition to cytotoxic therapy with CAF was evaluated against treatment with Ovx and CAF alone in 214 premenopausal patients with metastatic breast cancer from June, 1979 to September 1985. In addition to Ovx, all patients received cycles of CAF consisting of Cyclophosphamide, 400mg/m2 d. 1+8 iv. , Adriamycin, 25mg/m* d.1+8 i.v., and + 5-Fluorouracil, 500mg/mz i.v; Tamoxifen treatment was 30 mg p.d. until PD. All patients had measurable and/or evaluable lesions according UICC, a performance status of =< 3 and were without prior systemic treatment for recurrent disease. The treatment results were the following:
three 1 5 5 4
Median (days)
Our observations differ from other authors, and find that node negativity is associated with microcalcification. In conclusion, women with screen detected breast cancer of less than 1 cm in size, or those with Grade I tumours less than 3 cm could avoid axillary surgery, with a reduction in operating time and morbidity. Statistics by Chi-Squared analysis with Yates correction.
Ovx+CAF Ovx+CAF+T
Primary medical (neoadjuvant) chemotherapy (PMC) is being widely investigated as an alternative to mastectomy in patients with large operable breast carcinomas for whom conservative surgery is technically inappropriate. In an initial study we treated 45 patients with conventional combination chemotherapy (CT) (either cyclophosphamide 1OOmg orally days 1-14, methotrexate 30mg/m* iv days 1 & 8 and 5FU 6OOmg/mz iv days 1 & 8; or mitozantrone 8mg/m* iv q 3 weeks, methotrexate 30mg/m2 q3 weeks and mitomycin-C-8mg/m* iv q 6 weeks). Median age was 45 (range 23-65) years. 31 (69%) achieved an objective response (OR) with 7 (16%) achieving complete remission (CR). Subsequent radio-therapy increased the OR rate to 94% and CR to 43%. So far only 9% have required mastectomy. More recently, patients have been treated with a new infusional 5FU regimen (2OOmg/m2/24 hrs x 6 months by portable pump and Hickman line) in combination with epirubicin 50mg/m2 and cisplatin 60mg/m2 q 3 weekly. 10 out of 10 patients (100%) so far treated have responded
No. evaluable 108 98
CR 31 23
PR 31 35
NC 28 27
PD 18 13
TTP 460 560
Surv. 695 785
The rate of response was not improved by adding T to Ovx + CAF (57% vs. 59%, 95%C.L. of the diff.:-12%-15%). However, after progression of almost 90% of the pts., time to progession (‘lTP) was better in patients receiving of Twim Ovx+CAF (p=O.O4). Further, there is a trend for prolonged survival in this treatment group (p=O.O6) despite the fact that 50% of the pts. in the Ovx + CAF group received T upon progression.
65 PRIMARY MEDICAL (NEOADJUVANT) CHEMOTHERAPY FOR OPERABLE BREAST CANCER: BUILDING ON EARLY PROMISE Smith IE, Maclennan K, Dowsett M, McKinna JA, Sacks N, Baum M Royal Marsden Hospital London, UK
No. entered 110 104
67
TEN YEAR RESULTS OF THE CRC ADJUVANT BREAST TRIAL Riley D, Houghton J, Baum M on behalf of the CRC Breast Cancer Trials Group, CRC Clinical Trials Centre, London, UK Between 1980 and 1985, 2,230 patients with early breast cancer were randomized into a 2x2 factorial trial to investigate 6 days of perioperative cyclophosphamide or two years of adjuvant tamoxifen at 20mg per day. Despite early promising results, cyclosphosphamide fails to demonstrate any significant advantages over control with regards to DFS or overall survival. This paper concentrates on the “main effect” analyses for tamoxifen with 1.9 12 patients at a median follow-up of 7.8 years (5.8-11). Overall there has been a 27% reduction in the risk of relapse for the tamoxifen treated group. This benefit appears for all subgroups irrespective of major prognostic factors.
60 QUANTITATION OF AROMATASE CYTOCHROME P450 mRNA LEVELS IN HUMAN BREAST TUMOURS, USING A COMPARATIVE PCR TECHNIQUE Aitken, J. I*, Hardy, S.C.2, Parbhoo, S.P.2, Cooke, B.A. 1, Simpson, E.tZ.3 Departments of Biochemistry’ & Surgery*, Royal Free Hospital Medical School, Pond Street, London, NW3, UK. Department of Obstetrics & Gynaecology3, University of Texas Southwestern Medical Center, Da//as, Texas, USA Aromatase cytochrome P450 is the final enzyme in the pathway from C I9 androgens to C I8 oestrogens. Approximately I /3 of human breast cancers are oestrogen sensitive. We have previously shown. using the aroma&e tritiated water release assay, that 30% of breast turnour have detectable levels of aromatase activity and hence. the capacity to synthesise oestrogens. As the aromatase assay may not be sensitive enough to detect low levels of the enzyme in small amount!, of tissue, a comparative PCR technique was employed to measure mRNA. levels encoding aromatase in tumour tissue from 12 patients. Rat aromatase cRNA was coamplified as an internal standard to compare amplitication reactions. More patients were shown to be positive for aromatase mRNA (9/l?) compared to aromatase activity (7/121. However, there was no correlation between level. of mesrage and enzyme activity (S=-28. z=- I .c)l:P > 0.05 ). The ability to use the PCR technique to demonstrate expression of aromatase mRNA v+ould also lend itself to assaying material from needle biopsy specimens, thus allowing more appropriate selection of patients for treatment with aromatase inhibitors.
61 THE ROLE OF INTERLEUKIN-6 IN REGULATING BREAST TISSUE AROMATASE ACTIVITY
I6 I
using an explant culture system. Production of IL-6 by tumour tissue (232 + 226 rig/g.. mean *SD.. n = 6) was significantly higher (p
COMBlNAT[ON
OF
THE
AROMATASE
INHIBITORS 4HYDROXYANDROSTENEDIONE (40HA) AND AMINOGLUTHETHIMIDE (AG): AN APPROACH TO MAXIMIZATION OF AROMATASE INHIBITION AND E2 SUPPRESSION? MacNeill F, Dowsett M, Jacobs S, l Lonning P, Pow/es TJ Royal Marsden Hospital, London and Sutton, UK *Haukeland Sykehus, N-5021 Bergen, Norway Aromatase inhibitor is a clinically effective treatment for postmenopausal women with advanced breast cancer. It is not known if there is a direct relationship between aromataqc inhibition. E2 An early limited pilot study suppreaion and clinical response. suggested that sequential combination of 3OHA and AG, aromatase inhibitors with different modes of action, resulted in additional E? suppression with corresponding further climcal responses. This current study was performed to explore further the existence of any link between E7 suppression and additional aromatase inhibition. Ten postmenopausal women with advanced breast cancer received 4OHA 500mg irn weekly for a minimum of S-6 week\ after which AG IOOOmg daily was added. In-vivo istotope aromalase measurement studies were performed pre-treatment. on 40HA and on 40HA/AG combined. Regular plasma samples were taken for endocrine analysis (oestradiol E2). Mean % aromatase inhibition and E? suppression for 40HA 5OOmg im weekly was 91.1% (SEM + 2.5 1and 71.4% (SEM ? 4. I ) respectively. For combined therapy it wa\ Y2.X’I tSEM* 2.3) and 78.1% (SEM + 3.4) respectively. There was no \tati\tically signiiicant difference for either aromatase inhibition or E2 suppression between single and combination therapy. Although in keeping with the previous pilot study a difference between 40HA ‘tnd IOHA/AG E7 suppression of 26.4% (SEM + 7.5) was noted even though aromatase inhibition was unchanged. As expected aromatabe inhibition and E2 suppression by 4OHA are comparable to the prototype inhibitor AG. Combining the two drugs does not produce any statistically detectable difference. The increase in E? suppreahion measured on combination therapy whilst not statistically significant reHect\ _I real trend and i\ consequent upon AG stimulating oestrogen liver metabolism. The lack of correlation between E2 suppression and aromatase inhibition noted in the past has been confirmed in this study. There is no advantage in using a combination of AG/4OHA.
63 OESTRONE-3METHYLPHOSPHONOTHIOATE (ElMPT ) IS Reed, M J, Coldham, NG and Ghilchik M W Unit of Metabolic Medicine and The Breast Clinic, St. Mary’s A POTENT INHIBITOR OF OESTRONE Hospital Medical School, London, UK SULPHATASE ACTIVITY IN MCF-7 HUMAN BREAST CANCER CELLS The aromatase enzyme complex, which converts androstenedione to oestrone. is present in normal and malignant breast tissues and it is possible that factors produced by breast tumours increase aromatase activity in tissues adjacent to the tumour. To investigate such a possibility. the ability of conditioned medium (CM) from cultured tumour derived libroblasts or breast tumour cytosol (BTC) to stimulate aromatase activity in breast cancer cells was examined. Both CM and BTC were found to significantly stimulate aromatase activity and interleukin-6 (IL-6) has now been identified as a factor present in CM from tumour derived fibroblasts which stimulates aromatase activity. The production of IL-6 by breast tumour and normal breast tissues. obtained from patients undergoing mastectomy. has been examined
A. Purohit, L.J. Duncan and M.J. Reed Unit of Metabolic Medicine, St Mary’s Hospital School & Imperial College, London, UK
Medical
Oestrone sulphate stimulates the growth of breast tumours via conversion to oestrone and oestradiol as shown by data from a variety of in vitro and in vivo studies. Oestrone sulphatase. the enzyme which converts oestrone sulphate into oestrone, i\ consistently found in primary mammary carcinoma. This oestrone sulphatase pathway may, therefore. be significant and perhaps the primary means of local produc-
162
The Breast
tion of oestrone in breast tissues. We have synthesized EIMPT, a steroidal competitive inhibitor of oestrone sulphatase activity. In intact MCF-7 breast cancer cells in culture, ElMPT inhibited oestrone sulphatase activity in a dose-dependent mamter. The sulphatase activity in the absence of ElMPT was 89.4 +I- 5.2, 23.5 +I-3.0 and 3.6 +I- 0.2 fmol/2Oh006 cells respectively. Using 1OuM ElMPT, 96% inhibition of oestrone sulphatase activity was achieved. In contrast, Danazol, reported to inhibit the sulphatase, only inhibited oestrone sulphatase by 40% when tested at the same concentration. Furthermore, ElMPI was resistant to metabolism to oestrone in the presence of liver or placental microsomes. The development of inhibitors of oestrone sulphatase represents a novel therapeutic strategy to oestrogen-dependent breast cancer.
64 SHOULD THE AXILLA BE DISSECTED IN SCREEN DETECTED BREAST CANCER? J Walls, CRM Boggis, M Wilson, DL Asbury, JV Roberts, NJ Bundred, RE Manse1 Department of Surgery and Radiology, University Hospital of South Manchester, UK
including 6 (60%) achieving CR. Median initial tumour diameter was 6cm (range 5-9cm). Marked histological down-grading has been seen on serial biopsy with most patients showing only residual scar tissue and scattered isolated malignant cells. Primary medical chemotherapy for large operable breast cancer is effective in preventing mastectomy in the large majority of patients. Early results with infusional CT are encouraging and indicate the need for randomised comparison with conventional CT, it is possible that infusional CT may entirely replace surgery for some patients. This approach also offers a useful “test-bed” for promising new regimens prior to use as adjuvant therapy.
66 TAMOXIFEN AND CASTRATION IN ADDITION TO CYTOTOXICS IN THE TREATMENT OF PREMENOPAUSAL PATIENTS WITH METASTATIC BREAST CANCER. A phase Ill trial of CAF + castration vs CAF + castration + Tamoxifen Rose C, Andersson M, Mouridsen H T, Mailer K Aa, Overgaard M, Larsen PM, Dombernowsky P, Bastholt L, Christensen I, on behalf of the DBCG, Denmark Department of Oncology, Odense University Hospiral, Denmark
The management of axillary nodes in screen detected breast cancer is controversial. Optimal treatment should combine accurate node status with the avoidance of unnecessary morbidity. The aim of this study was to determine if full axillary dissection can be avoided in some women with screen detected cancer. Since October, 1988, 223 breast cancers have been discovered via the screening programme. 180 were invasive, of which 22% were found to be lymph node positive. The presence of involved nodes was associated with large tumour size (p < O.OOS), high grade (p < O.Ol), and the absence of tumour microcalcification (p < 0.05). (see table below; microcalcification data not shown) Pathological tumour size
Grade of tumour
Number of involved axillae by grade
one 16 25 4 4
one 0 1 0 2
two 11 46 15 12
three 3 11 7 6
two 0 10 6 6
The efficacy of combined endocrine therapy with ovarian irradiation (Ovx) and Tamoxifen (T) in addition to cytotoxic therapy with CAF was evaluated against treatment with Ovx and CAF alone in 214 premenopausal patients with metastatic breast cancer from June, 1979 to September 1985. In addition to Ovx, all patients received cycles of CAF consisting of Cyclophosphamide, 400mg/m2 d. 1+8 iv. , Adriamycin, 25mg/m* d.1+8 i.v., and + 5-Fluorouracil, 500mg/mz i.v; Tamoxifen treatment was 30 mg p.d. until PD. All patients had measurable and/or evaluable lesions according UICC, a performance status of =< 3 and were without prior systemic treatment for recurrent disease. The treatment results were the following:
three 1 5 5 4
Median (days)
Our observations differ from other authors, and find that node negativity is associated with microcalcification. In conclusion, women with screen detected breast cancer of less than 1 cm in size, or those with Grade I tumours less than 3 cm could avoid axillary surgery, with a reduction in operating time and morbidity. Statistics by Chi-Squared analysis with Yates correction.
Ovx+CAF Ovx+CAF+T
Primary medical (neoadjuvant) chemotherapy (PMC) is being widely investigated as an alternative to mastectomy in patients with large operable breast carcinomas for whom conservative surgery is technically inappropriate. In an initial study we treated 45 patients with conventional combination chemotherapy (CT) (either cyclophosphamide 1OOmg orally days 1-14, methotrexate 30mg/m* iv days 1 & 8 and 5FU 6OOmg/mz iv days 1 & 8; or mitozantrone 8mg/m* iv q 3 weeks, methotrexate 30mg/m2 q3 weeks and mitomycin-C-8mg/m* iv q 6 weeks). Median age was 45 (range 23-65) years. 31 (69%) achieved an objective response (OR) with 7 (16%) achieving complete remission (CR). Subsequent radio-therapy increased the OR rate to 94% and CR to 43%. So far only 9% have required mastectomy. More recently, patients have been treated with a new infusional 5FU regimen (2OOmg/m2/24 hrs x 6 months by portable pump and Hickman line) in combination with epirubicin 50mg/m2 and cisplatin 60mg/m2 q 3 weekly. 10 out of 10 patients (100%) so far treated have responded
No. evaluable 108 98
CR 31 23
PR 31 35
NC 28 27
PD 18 13
TTP 460 560
Surv. 695 785
The rate of response was not improved by adding T to Ovx + CAF (57% vs. 59%, 95%C.L. of the diff.:-12%-15%). However, after progression of almost 90% of the pts., time to progession (‘lTP) was better in patients receiving of Twim Ovx+CAF (p=O.O4). Further, there is a trend for prolonged survival in this treatment group (p=O.O6) despite the fact that 50% of the pts. in the Ovx + CAF group received T upon progression.
65 PRIMARY MEDICAL (NEOADJUVANT) CHEMOTHERAPY FOR OPERABLE BREAST CANCER: BUILDING ON EARLY PROMISE Smith IE, Maclennan K, Dowsett M, McKinna JA, Sacks N, Baum M Royal Marsden Hospital London, UK
No. entered 110 104
67
TEN YEAR RESULTS OF THE CRC ADJUVANT BREAST TRIAL Riley D, Houghton J, Baum M on behalf of the CRC Breast Cancer Trials Group, CRC Clinical Trials Centre, London, UK Between 1980 and 1985, 2,230 patients with early breast cancer were randomized into a 2x2 factorial trial to investigate 6 days of perioperative cyclophosphamide or two years of adjuvant tamoxifen at 20mg per day. Despite early promising results, cyclosphosphamide fails to demonstrate any significant advantages over control with regards to DFS or overall survival. This paper concentrates on the “main effect” analyses for tamoxifen with 1.9 12 patients at a median follow-up of 7.8 years (5.8-11). Overall there has been a 27% reduction in the risk of relapse for the tamoxifen treated group. This benefit appears for all subgroups irrespective of major prognostic factors.