I.  Tamoxifen
     A.  An Antiestrogen or selective estrogen receptor modulator
	 (SERM)
          1.  Has both estrogenic and antiestrogenic effects
               a.  Estrogenic - Bone, liver, uterus
               b.  Antiestrogenic - breast, brain, vaginal mucosa
          2.  Inhibits the growth of hormone-responsive human 
	       breast cancer cells in vitro
          3.  Effect is modulated through the estrogen receptor
	       (ER) and interactions with other cytokines

II.  Treatment of Metastatic Breast Cancer1
     A.  Beatson first described a patient with breast cancer in 
	  whom oophorectomy caused regression of skin metastases
	  in 1896.
     B.  Tamoxifen is the first choice in endocrine therapy for 
	  metastatic breast cancer in both pre- and post-menopausal 
	  women
          1.  Favorable toxicity profile
          2.  High response rates as initial therapy
               a.  In unselected patients, response rates range
		    from 30-40%, with response durations 
		    averaging about one year
               b.  Fifty percent of patients whose tumors are 
		    ER+ respond.
               c.  Response rate is 10-15% in hormone receptor
		    negative metastatic breast cancer
               d.  The withdrawal of therapy also yields responses
		    in as many as 20% of patients whose tumors 
		    initially regress then later progress on 
		    tamoxifen
     C.  In about 5% of patients with skin/bone metastases, 
	  tamoxifen causes a tumor 'flare' with an increase 
	  in size, number, & discomfort of skin lesions and
	  by increasing bone pain and/or hypercalcemia
          1.  Such reactions generally occur within days or
	       weeks of treatment initiation
          2.  Flare reactions usually portend a good response 
	       to tamoxifen

III.  Adjuvant Therapy for Breast Cancer - EBCTCG overview, 19982
     A.  Included 37,000 women in 55 trials with 10 years
	  follow-up
     B.  Nearly 8000 women in the overview analysis had low, 
	  or zero,level of ER measured in their primary tumor. 
	  Among them, the overall effects of tamoxifen appeared 
	  to be small, if any.
     C.  Women with ER+ tumors derive great benefit from 
	  adjuvant tamoxifen
          1.  5 years of tamoxifen is better than 1 or 2
          2.  The absolute benefit in recurrence was greater
	       during the first 5 years, whereas the 
	       improvement in survival grew steadily larger 
	       throughout the first 10 years.
          3.  The proportional benefit was similar in 
	       node-positive and node-negative disease
          4.  The benefits were evident regardless of age, 
	       menopausal status, or whether chemotherapy 
	       had been given.
     D.  Contralateral breast cancer rates lower in women who had 
	  received tamoxifen
     E.  Toxicity
          1.  Endometrial cancer rates were higher in women who 
	       took tamoxifen
          2.  Tamoxifen had no effect on colon cancer incidence
          3.  The difference in non-breast cancer mortality 
	       between tamoxifen and control was not significant
	       for any other categories than endometrial cancer.
                 a.  Cardiac
                 b.  Vascular
                 c.  Pulmonary embolus
                 d.  Eye changes - see Ophthalmologist yearly

IV.  Tamoxifen for Ductal Carcinoma In Situ -NSABP B-243
     A.  Randomized 1804 women with DCIS who had lumpectomy 
	    followed by local adjuvant radiation therapy to
	    Tamoxifen or Placebo
            1.  Included women whose resected sample margins were
		 involved with tumor
     B.  Women in the tamoxifen group had fewer breast cancer
	    events at 5 years than those in the placebo group 
	    (rate ratio 0.63, 95% CI 0.47-0.83)
            1.  Fewer ipsilateral events
		 (rate ratio 0.70, 95% CI 0.50-0.98)
            2.  Fewer contralateral events
		 (rate ratio 0.48, 95% CI 0.26-0.87)
     C.  There was no statistically significant increase in 
	    non-breast cancer events
            1.  Second primary cancers other than endometrial 
		 cancer
            2.  Endometrial cancer
            3.  Deaths, no evidence of cancer

V.  Tamoxifen to Decrease the Incidence of Breast Cancer4
     A.  NSABP  P-1
            1.  Randomized 13,338 women at high risk for breast 
		 cancer to tamoxifen or placebo for 
		 5 years -  5.75 years of follow-up
		 (mean 47.7 months)
            2.  Tamoxifen decreased the incidence of invasive and 
		 non-invasive breast
		 cancer in all groups
            3.  The bone fracture rate was lower on tamoxifen
            4.  Most of the toxicities were limited to women over
		 age 50 years
                 a.  More endometrial cancer
                 b.  More thromboembolic events
     B.  Royal Marsden Breast Cancer Prevention Trial
            1.  Randomized 2471 women, at high risk based on fam.
		 hx, to tamoxifen or placebo
                 a.  Allowed HRT
                 b.  Median follow-up 5.8 years
            2.  No difference in breast cancer incidence
            3.  Increased hot flashes & gynecologic problems led to 
		 discontinuation of tamoxifen
            4.  Very few adverse events
     C.  Italian Breast Cancer Prevention Trial
            1.  Randomized 5408 women, who were S/P hysterectomy,
		to tamoxifen or placebo
                 a.  Allowed HRT
                 b.  Median follow-up 3.8 years
                 c.  23 .6% dropped out
            2.  No significant difference in breast cancer rates
            3.  Incidentally noted decrease breast cancer rate in 
		 women taking HRT
            4.  Women on tamoxifen had more phlebitis 
		 (but not statistically more DVT or PE)