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576 Chemo-hormonal therapy of mouse mammary tumors
576
Chemo-hormonal Mels Sluyser,
therapy
of mouse mammary
The Netherlands
Cancer
tumors
Institute,
Amsterdam.
In 1974 it was demonstrated that hormone-responsive GR mouse mammary tumors are mixed populations of ER-positive and ER-negative cells, and that only the formercells respond to hormonal therapy (M. Sluyser and R. van Nie, Cancer Res. 1974: 34, 3253). We therefore proposed that combined hormonal treatment and chemotherapy of hormone responsive breast cancers might be more effective than either treatment given alone. GR mouse mammary tumors represent a useful model system to study the effect of different treatment combinations, because heterogeneous mammary cancers of various compositions can be compared.Comparison of various transplant generations indicates that heterogeneousmammary tumors are especially susceptible to cytotoxic chemotherapy at the transition stage from hormone dependence to independence i.e. when the first independent indicates that therapy modalities of mammary cancer cell clones emerge. This result shouldbe adapted to the progression state of the tumor in question. Tamoxifen and 4-monohydroxytamoxifen inhibit the growth of hormone-responsive mouse mammary tumors. Monohydroxytamoxifen is more potent than tamoxifen when administered in pellets S.C. Neither drug inhibits hormone-independent mammary tumors. Combined therapy of mouse mammary tumors with cyclophosphamide and tamoxifen is more effective than either treatment qiven singly.
577
RATIONALE
FOR COMBINING
CHEMOTHERAPY
AND HORMONAL
THERAPY
ROSS0 R., SERTOLI M.R., SCARS1 P.G., Istituto Nazionale Istituto di Oncologia dell'universita, Genova, Italy.
IN BREAST CANCER.
per la Ricerca
sul Cancro,
Rationale for an additive effect of combining chemo-hormonotherapy in the treatment of breast ca. is based on a series of biological and clinical evidences: 1)chemotherapy (CT) and hormonotherapy (HT) have reached a plateau concerning response rate, duration and survival; 2)every breast ca. must be considered representative of an heterogeneous population of ER+ and ER- cells; 3)preliminary data indicate that probably CT and HT act on different fractions of cancer cell population; 4)different mechanisms of action without any overlappig toxicity; 5)controlled studies indicate the significantly higher response rate obtained in the combination modality in respect to the single modality. Open question concerns what is the best timing for combining CT and HT: simultaneously, sequentially, alternating. On the basis of the data up to now available, it seem that simultaneous combination can be recommended for every patient with doesn't breast ca.; probably only aggressive disease justifies this approach because the higher response rate that can be achieved. It is possible that receptors determination and cytokinetic parameters can allow individualization of the disease and represent the basis for individualized medical treatment.
578
ADJWANT CHEMOTHERAPY AND HORMONAL THERAPY FOR OPERABLE BREAST CANCER WITH POSITIVE AXI S.Knight,Mary Foulkes. Tumor Institute of Swedish Ho LLARY NODES. Saul E.Rivkin,William spital Medical Center,Seattle,Washington;University of Texas,Health Science Center at San Antonio,Texas and Southwest Oncology Group Statistical Center,Houston,Texas. Women with operable breast cancer with axillary N+ were randomized on the basis of ER status,menopausal status and number of involved nodes (l-3 and >4). Pts.receiving a ra= dical,modified radical or tylectomy with primary radiation therapy were randomized and initiated on therapy within 42 days after surgery. CMFVP:CYC(~O mg/mq po daily);5-FU (400 mg/mq IV weekly);MTX(15 mg/mq IV weekly);VCR(0.625 mg/mq IV weekly x 10 wks);PRD (30 ms/mq days l-14;20 mg/mq days 15-28;lO mg/mq days 29-42 po and discontinued there= after);Tamoxifen(lO mg po twice daily for 1~). A total of 614 fully evaluable pts. have been randomized between July 1979 and January 1983. POST ER+ PRE-POST ERERPRE (CMFVPT vs.T vs.CMFVP) (CMFVP “S .OVT+CMFVP) (CMFVP:ly vs.2ys) FULLY
EVAL.
RELAPSES
145
144
37
33
83
87
85
27
21
6
2
7
9
9
From preliminary data it appears that ER- pts.have (p = 0.025). To date,there has been no significant (Supported in part by NC1 grant CA 20319).
a higher relapse rate than ER+ pts. differnce in the 3rd study.
Chemo-hormonal Mels Sluyser,
therapy
of mouse mammary
The Netherlands
Cancer
tumors
Institute,
Amsterdam.
In 1974 it was demonstrated that hormone-responsive GR mouse mammary tumors are mixed populations of ER-positive and ER-negative cells, and that only the formercells respond to hormonal therapy (M. Sluyser and R. van Nie, Cancer Res. 1974: 34, 3253). We therefore proposed that combined hormonal treatment and chemotherapy of hormone responsive breast cancers might be more effective than either treatment given alone. GR mouse mammary tumors represent a useful model system to study the effect of different treatment combinations, because heterogeneous mammary cancers of various compositions can be compared.Comparison of various transplant generations indicates that heterogeneousmammary tumors are especially susceptible to cytotoxic chemotherapy at the transition stage from hormone dependence to independence i.e. when the first independent indicates that therapy modalities of mammary cancer cell clones emerge. This result shouldbe adapted to the progression state of the tumor in question. Tamoxifen and 4-monohydroxytamoxifen inhibit the growth of hormone-responsive mouse mammary tumors. Monohydroxytamoxifen is more potent than tamoxifen when administered in pellets S.C. Neither drug inhibits hormone-independent mammary tumors. Combined therapy of mouse mammary tumors with cyclophosphamide and tamoxifen is more effective than either treatment qiven singly.
577
RATIONALE
FOR COMBINING
CHEMOTHERAPY
AND HORMONAL
THERAPY
ROSS0 R., SERTOLI M.R., SCARS1 P.G., Istituto Nazionale Istituto di Oncologia dell'universita, Genova, Italy.
IN BREAST CANCER.
per la Ricerca
sul Cancro,
Rationale for an additive effect of combining chemo-hormonotherapy in the treatment of breast ca. is based on a series of biological and clinical evidences: 1)chemotherapy (CT) and hormonotherapy (HT) have reached a plateau concerning response rate, duration and survival; 2)every breast ca. must be considered representative of an heterogeneous population of ER+ and ER- cells; 3)preliminary data indicate that probably CT and HT act on different fractions of cancer cell population; 4)different mechanisms of action without any overlappig toxicity; 5)controlled studies indicate the significantly higher response rate obtained in the combination modality in respect to the single modality. Open question concerns what is the best timing for combining CT and HT: simultaneously, sequentially, alternating. On the basis of the data up to now available, it seem that simultaneous combination can be recommended for every patient with doesn't breast ca.; probably only aggressive disease justifies this approach because the higher response rate that can be achieved. It is possible that receptors determination and cytokinetic parameters can allow individualization of the disease and represent the basis for individualized medical treatment.
578
ADJWANT CHEMOTHERAPY AND HORMONAL THERAPY FOR OPERABLE BREAST CANCER WITH POSITIVE AXI S.Knight,Mary Foulkes. Tumor Institute of Swedish Ho LLARY NODES. Saul E.Rivkin,William spital Medical Center,Seattle,Washington;University of Texas,Health Science Center at San Antonio,Texas and Southwest Oncology Group Statistical Center,Houston,Texas. Women with operable breast cancer with axillary N+ were randomized on the basis of ER status,menopausal status and number of involved nodes (l-3 and >4). Pts.receiving a ra= dical,modified radical or tylectomy with primary radiation therapy were randomized and initiated on therapy within 42 days after surgery. CMFVP:CYC(~O mg/mq po daily);5-FU (400 mg/mq IV weekly);MTX(15 mg/mq IV weekly);VCR(0.625 mg/mq IV weekly x 10 wks);PRD (30 ms/mq days l-14;20 mg/mq days 15-28;lO mg/mq days 29-42 po and discontinued there= after);Tamoxifen(lO mg po twice daily for 1~). A total of 614 fully evaluable pts. have been randomized between July 1979 and January 1983. POST ER+ PRE-POST ERERPRE (CMFVPT vs.T vs.CMFVP) (CMFVP “S .OVT+CMFVP) (CMFVP:ly vs.2ys) FULLY
EVAL.
RELAPSES
145
144
37
33
83
87
85
27
21
6
2
7
9
9
From preliminary data it appears that ER- pts.have (p = 0.025). To date,there has been no significant (Supported in part by NC1 grant CA 20319).
a higher relapse rate than ER+ pts. differnce in the 3rd study.