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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: squetch who wrote (15144)	2/15/1998 5:39:00 PM
From: Andrew H	Respond to of 32384

>>Fifteen of 39 patients (38%) who received tamoxifen experienced an objective tumor regression (3 complete<< 3 of 39 patients given Tamoxifen experienced a complete tumor regression. Unfortunately, we don't know if these patients had multiple tumors or not. Chances are many did. In any case, we can see that there was a far smaller percentage of complete remission in human beings than there was in rats.

To: squetch who wrote (15144)	2/16/1998 8:38:00 AM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

Stan, Most of the references that you gave were from the late 70's, early 80's. Clinical protocols are out of my area and I haven't had a chance to look up specific references, so I'll just post a general impression that I have, subject to modification by me or others. Estrogen, like the molecules that LGND synthesize for use in their IR technology, is a small molecule that acts by first binding to it's receptor(s) which are inside cells, including breast. The binding can stimulate the cells to divide, and in some cases, breast cancers is thought to be due to such a stimulation that is out of control. Tamoxifen can also bind to this receptor and block estrogen from binding, so it is considered an anti-estrogen for breast. However, it has the undesired property of binding to the receptor in uterine cells and causing them to divide, resulting in endometrial cancer. Breast cancer cells can lose their estrogen receptor and therefore they can be classified as ER+ (still have the receptor) or ER- (lost the receptor). I believe that Tamoxifen was initially recommended for ER+ tumors (because the above model would predict that it was ineffective in ER- tumors because there was no receptor). I believe that it was also recommended for use as adjuvant therapy after surgery and radiation and/or chemotherapy, because it was more effective on residual tumor cells than primary treatment for a large or many smaller tumors. However, more recent studies (earlier 90's) indicated that Tamoxifen could also be effective against ER- tumors, so the target population was changed to all breast cancer, regardless of ER status. Recently, a long term study indicated that Tamoxifen produced no measurable benefit when used for more than 5 years.

To: squetch who wrote (15144)	2/16/1998 3:54:00 PM
From: Henry Niman	Respond to of 32384

Here's a more recent article on Tamoxifen and Chemotherapy: J Natl Cancer Inst 1997 Nov 19;89(22):1673-1682 Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh, PA, USA. BACKGROUND: The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. METHODS: Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. RESULTS: Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen [P = .001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemotherapy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. CONCLUSIONS: Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy. Publication Types: Clinical trial Randomized controlled trial Comments: Comment in: J Natl Cancer Inst 1997 Nov 19;89(22):1652-4 PMID: 9390536, UI: 98050902

To: squetch who wrote (15144)	2/16/1998 3:57:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's the paper showing no additional benefit after 5 years of Tamoxifen: J Natl Cancer Inst 1996 Nov 6;88(21):1529-1542 Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschenes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AH, Feldman MI, Farrar W, Evans J, Lickley HL University of Pittsburgh School of Medicine, PA 15261, USA. BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years. Publication Types: Clinical trial Multicenter study Randomized controlled trial Comments: Comment in: J Natl Cancer Inst 1996 Nov 6;88(21):1510-2 Comment in: J Natl Cancer Inst 1997 Nov 5;89(21):1631-2 PMID: 8901851, UI: 97057512