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Adjuvant treatment in operable breast cancer: The ludwig breast cancer trials
Abstracts
IN VITRO SYNERGISM BETWEEN CYTOTOXIC AND HORMONAL AGENTS. G.Leclercq - Institut J. Bordet - Brussels - Belgium.
Estrogens bind to cytoplasmic estrogen receptors (ER); the resulting complexes are then translocated to the cell nucleus where they produce structural modifications of the chromatin. In relation with this mechanism, two main lines of research are pursued in our laboratory to achieve synergism between cytotoxic and hormonal agents. 1. To produce cytotoxic-linked estrogens which bind to ER and are selectively concentrated into the tumor cells. The measurement of the binding affinity of such drugs for ER as well as the evaluation of their cytotoxicity on breast cancer cell lines containing (MCF-7) or lacking (Evsa-T) the receptors provide a very efficient screening procedure. Guide-lines for the synthesis of new drugs emerge from these investigations. 2. To increase the vulnerability of the tumor cells to intercalating agents by producing an estrogen-induced modification of the chromatin. We have found that exposure of isolated uterine nuclei to uterine cytosol preincubated with estradiol causes a significant increase in their ability to bind 3H-actinomycin D. Worthy of note, hydroxytamoxifen was ineffective and antagonized the effect of estradiol. Investigation on isolated nuclei from MXT mouse mammary tumors gave identical results. Whether this increase might be associated with a higher cellular vulnerability to intercalating agents will be analysed.
SURVIVAL DATA OF A COMBII~ATION VERSUS SEOUEMTIAL HORNONAL THERAPY AtlD CYTOTOXIC CHEflOTHERAPY III ADVAtlCED BREAST CANCE!?. David T. Kianq, M.D., Ph.D., and B. J. Kenned?/, il.D., University of I'iinnesota, Ilinneapolis, FlM, U.S.A.
The effectiveness of a combination therapy b.Gth diethylstilbestrol, cyclophosphamide, and 5-fluorouracil (DES+CTx+FU) was comoared with DES alone or CTx+FU in 112 postmenooausal patients with advanced breast cancer. Therapy was randomized according to tumor estrogen receptor (ER) status. We have previously reported that the combination reoimen provided a significantly higher complete and partial response rate than szauential therapy in patients with ER (+) and ER-unknown tumors (Cancer 47:452-W 1981). This communication provided the survival data of the st.uay initiated leven years ago. Of the 22 patients in the ER (+) group receiving DES+CTx+FU, the survival curve leveled off at 51% by 3% years and maintained at this level us to 7 years; while the median survival for 19 ER (+) patients receivinn sequential hormone therapy and chemotherapy was 24 years (P aoproaching 0.05). The survival data for 30 patients with ER (-) tumors were uniformly poor, with a median survival of 1% years, regardless of the therapeutic modality. For the 41 patients with ER-unknown tumors, survival advantage from the combination therapy was seen in the first three years and then disappeared.
ADJUVANT TREATMENT IN OPERABLE BREAST CANCER:THE LUDWIG BREAST CANCER TRIALS. Ludwig Breast Cancer Study Group (presented by Dr.Aron Goldhirsch).
In July,1978,the Ludwig Breast Cancer Study Group initiated 4 randomized trials to evaluate combinations of hormonotherapy and chemotherapy or hormonotherapy alone within su bgroups of pts. with operable breast cancer. Participating centers,entered 1713 pts. in to the four trials until August,l981. The four studies are:LCBS I:N+(l-3) CMF vs.CMFp;LCBS II:N+(>A) CMFp vs. OVC + CMFp; LCBS 111465 ys. CWpT vs. pT vs. Obs.; LCBS IVz>65 ys. pT VS. Obs. In IBCS III a combination of chemotherapy,S-Fluorouracil(F) with Cycle phosphamide (C),Methotrexate (M),prednisone (p) and Tamoxifen (T),for the duration of 12 monthly cycles was yompared to p and T alone for the same duration,and to mastectomy alone. 461 of 503 pts. (92%) were evaluable,and median follow-up as of March,l983,was 32 months. Preliminary results will be available.
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IN VITRO SYNERGISM BETWEEN CYTOTOXIC AND HORMONAL AGENTS. G.Leclercq - Institut J. Bordet - Brussels - Belgium.
Estrogens bind to cytoplasmic estrogen receptors (ER); the resulting complexes are then translocated to the cell nucleus where they produce structural modifications of the chromatin. In relation with this mechanism, two main lines of research are pursued in our laboratory to achieve synergism between cytotoxic and hormonal agents. 1. To produce cytotoxic-linked estrogens which bind to ER and are selectively concentrated into the tumor cells. The measurement of the binding affinity of such drugs for ER as well as the evaluation of their cytotoxicity on breast cancer cell lines containing (MCF-7) or lacking (Evsa-T) the receptors provide a very efficient screening procedure. Guide-lines for the synthesis of new drugs emerge from these investigations. 2. To increase the vulnerability of the tumor cells to intercalating agents by producing an estrogen-induced modification of the chromatin. We have found that exposure of isolated uterine nuclei to uterine cytosol preincubated with estradiol causes a significant increase in their ability to bind 3H-actinomycin D. Worthy of note, hydroxytamoxifen was ineffective and antagonized the effect of estradiol. Investigation on isolated nuclei from MXT mouse mammary tumors gave identical results. Whether this increase might be associated with a higher cellular vulnerability to intercalating agents will be analysed.
SURVIVAL DATA OF A COMBII~ATION VERSUS SEOUEMTIAL HORNONAL THERAPY AtlD CYTOTOXIC CHEflOTHERAPY III ADVAtlCED BREAST CANCE!?. David T. Kianq, M.D., Ph.D., and B. J. Kenned?/, il.D., University of I'iinnesota, Ilinneapolis, FlM, U.S.A.
The effectiveness of a combination therapy b.Gth diethylstilbestrol, cyclophosphamide, and 5-fluorouracil (DES+CTx+FU) was comoared with DES alone or CTx+FU in 112 postmenooausal patients with advanced breast cancer. Therapy was randomized according to tumor estrogen receptor (ER) status. We have previously reported that the combination reoimen provided a significantly higher complete and partial response rate than szauential therapy in patients with ER (+) and ER-unknown tumors (Cancer 47:452-W 1981). This communication provided the survival data of the st.uay initiated leven years ago. Of the 22 patients in the ER (+) group receiving DES+CTx+FU, the survival curve leveled off at 51% by 3% years and maintained at this level us to 7 years; while the median survival for 19 ER (+) patients receivinn sequential hormone therapy and chemotherapy was 24 years (P aoproaching 0.05). The survival data for 30 patients with ER (-) tumors were uniformly poor, with a median survival of 1% years, regardless of the therapeutic modality. For the 41 patients with ER-unknown tumors, survival advantage from the combination therapy was seen in the first three years and then disappeared.
ADJUVANT TREATMENT IN OPERABLE BREAST CANCER:THE LUDWIG BREAST CANCER TRIALS. Ludwig Breast Cancer Study Group (presented by Dr.Aron Goldhirsch).
In July,1978,the Ludwig Breast Cancer Study Group initiated 4 randomized trials to evaluate combinations of hormonotherapy and chemotherapy or hormonotherapy alone within su bgroups of pts. with operable breast cancer. Participating centers,entered 1713 pts. in to the four trials until August,l981. The four studies are:LCBS I:N+(l-3) CMF vs.CMFp;LCBS II:N+(>A) CMFp vs. OVC + CMFp; LCBS 111465 ys. CWpT vs. pT vs. Obs.; LCBS IVz>65 ys. pT VS. Obs. In IBCS III a combination of chemotherapy,S-Fluorouracil(F) with Cycle phosphamide (C),Methotrexate (M),prednisone (p) and Tamoxifen (T),for the duration of 12 monthly cycles was yompared to p and T alone for the same duration,and to mastectomy alone. 461 of 503 pts. (92%) were evaluable,and median follow-up as of March,l983,was 32 months. Preliminary results will be available.
vi