Radiation Oncology/Breast/Prevention

Prevention trials

 * Breast Cancer Prevention Trial (NSABP P-1), 1998 (1992-7)
 * 13000+ pts. Tested the hypothesis that tamoxifen could be used for breast cancer prevention. Enrolled high risk women who were 1) age 60 or older, 2) age 35-59 with a 5-year predicted risk of cancer of at least 1.66% (by Gail model), or 3) history of LCIS. Randomized to placebo vs tamoxifen 20 mg x 5 yrs.
 * PMID 9747868 Full text, 1998 &mdash; "Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study." Fisher B et al. J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88.
 * Reduced risk of invasive breast cancer by 49% (43.4 vs 22 per 1000). 56% reduction for pts with LCIS and 86% for atypical hyperplasia. Reduced non-invasive breast cancer by 50%. No difference in ER-negative tumors. Risk of endometrial cancer RR=2.53.  No decrease in ischemic heart disease events.  Decrease in bone fractures.
 * PMID 16288118, 2005 &mdash; "Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study." Fisher B et al. J Natl Cancer Inst. 2005 Nov 16;97(22):1652-62.
 * 7-yr f/u. Reduce rate of invasive cancer by 43% (42.5 vs 24.8 per 1000). Reduced non-invasive cancer by 37%. Reduced osteoporotic fractures by 32%.


 * STAR: Study of Tamoxifen and Raloxifene (NSABP P-2) (1999-2004)
 * Randomized to tamoxifen 20 mg or raloxifene 60 mg x 5 yrs. Entry criteria similar to BCPT except pre-menopausal women not allowed.
 * Target goal: 22,000 women.
 * PMID 16754727, 2006 &mdash; "Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial." Vogel VG et al. JAMA. 2006 June 21;295:2727-2741.
 * Raloxifene as effective as Tamoxifen in reducing risk of invasive breast cancer. Lower risk of thromboembolic events and cataracts. Higher risk of non-invasive cancer (but N.S.). Other effects are similar.
 * Quality of life: PMID 16754728, 2006 &mdash; "Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial." Land SR et al. JAMA. 2006 Jun 21;295:2742-2751.


 * IBIS-1 Internation Breast Cancer Intervention study, 2002
 * Similar to Breast Cancer Prevention Trial. Risk reduction of 32%. This is thought to be less than that in BCPT because there was less atypical hyperplasia in this trial.
 * PMID 12243915 &mdash; "First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial." Cuzick J et al. Lancet. 2002 Sep 14;360(9336):817-24.


 * Prophylactic Mastectomy (Hartmann, et al. NEJM 1999, 340, 77)·
 * Mayo Clinic data suggest a 90% reduction in risk of developing breast cancer
 * 639 moderate and high risk women underwent prophylactic mastectomy 1960 - 1993
 * this only applies to patients at moderate - high risk of developing breast by the Gail model
 * PMID 9887158

Raloxifene

 * PMID 16837684 - Risk-Benefit Profiles of Raloxifene for Women (Editorial) (Stefanick ML, NEJM 2006 Jul 13; 355(2):190-192)
 * RUTH: Raloxifene Use for the Heart (raloxifene 60mg in post-menopausal women at risk or with CHD)
 * CHD: no impact
 * BCA: -44% = 1.2 fewer cases per 1000 women/year
 * vertebaral fxs: -35% = 1.3 fewer cases per 1000 women/year
 * venous thromboembolism +44% = 1.2 excess cases per 1000 women/year
 * fatal stroke +49% = 0.7 excess cases per 1000 women/year
 * Conclusion : raloxifene BCA benefit probably not worth the risk in women at risk for CHD
 * Women's Health Initiative (postomenpausal women at average risk for BCA [trial placebo group], using raloxifene stats from RUTH)
 * BCA: 1.7 fewer cases per 1000 women/year
 * Conclusion : raloxifiene BCA benefit minimal in "average risk" postmenopausal women, given the risk
 * Breast Cancer Prevention Trial (tamoxifen in post-menopausal women at risk for BCA)
 * BCA: -49% = 3.3 fewer cases per 1000 women/year
 * STAR: Study of Tamoxifen and Raloxifene (women at high risk for BCA)
 * no placebo group; similar rates of invasive BCA => comparable efficacy of tamoxifen and raloxifene => ~3.3 fewer cases per 1000 women/year)
 * Editorial conclusion Raloxifene efficacy at preventing BCA vs. causing thromboembolism/stroke depends on level of BCA risk. It is probably not worth it for "average risk" post-menopausal women.

Guidelines

 * ASCO Clinical Practice Guideline
 * 2009 - PMID 19470930 link &mdash; "American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction." (Visvanathan K, J Clin Oncol. 2009 Jul 1;27(19):3235-58.)

Prophylactic Breast Irradiation

 * Israel BRCA1/2 (2007-2017) -- control (no RT) vs contralateral breast RT
 * Randomized Phase II. 162 patients, BRCA1/2 positive, early stage BCA, who declined contralateral mastectomy. Arm 1) no contralateral RT (control) vs Arm 2) Contralateral RT
 * 2019 PMID 30475942 -- "Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer" (Evron E, Ann Oncol. 2019 Mar 1;30(3):412-417.doi: 10.1093/annonc/mdy515.). Median F/U 4.8 years
 * Outcome: Contralateral BCA control 12% vs RT 2% (p=0.01). Median 2.7 years vs 7.7 years
 * Conclusion: Among BRCA carriers treated for early BCA, contralateral breast RT reduces contralateral breast cancers, and delays their onset


 * Columbia; 2007 PMID 17971581 -- "Reducing second breast cancers: a potential role for prophylactic mammary irradiation." (Brenner DJ, J Clin Oncol. 2007 Nov 1;25(31):4868-72.)
 * Suggestion of a potential benefit of low dose (17-22 Gy) ipsilateral (in case of APBI) and/or contralateral prophylactic breast irradiation