Global Breast Cancer Conference 2017 21 st Apr, 2017@Chezu Island Long Term Toxicity of Endocrine Therapy for premenopausal women with ER positive breast cancer Shinji Ohno, M.D., Ph.D., F.A.C.S. Breast Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research
Role of Estrogen Brain Helps maintain body temperature Prevents memory loss Heart & Liver Regulates cholesterol Reduces plaque build up in arteries Ovary Stimulates maturation Kickstarts menstrual cycle Vagina Stimulates maturation Maintains lubrication Thickens vaginal lining Breast Stimulates puberty Prepare milk glands Uterus Stimulates maturation Prepares uterus for fetus nourishment Bones Preserves bone mineral density
In view of the long life expectancy of young women, the panel reinforced the need to monitor potential long term toxicities (i.e. cardiovascular, bone morbidity, cognitive impairment).
In view of the long life expectancy of young women, the panel reinforced the need to monitor potential long term toxicity (i.e. cardiovascular, bone morbidity, cognitive impairment). Overall Survival 1.8.6.4.2 0 20 29 y.o. Cancer Institute Hospital (1945~2006, about 8,000 cases) 40 49 y.o. Years after operation 30 39 y.o. p<0.0001 0 10 20 30 40 50
Endocrine therapy for premenopausal women with ER positive breast cancer Premenopausal women with breast cancer may survive for a long period after primary treatment. Standard endocrine therapy for premenopausal women with ER+ breast cancer is tamoxifen for 5 to 10 years with or without LHRH agonists, and aromatase inhibitor with LHRH agonists for high risk cases. Endocrine therapy causes a variety of toxicities during the endocrine therapy. Little information is there about long term toxicity of endocrine therapy, which must be very important clinically.
Endocrine therapy for premenopausal women with ER positive breast cancer Premenopausal women with breast cancer may survive for a long period after primary treatment. Standard endocrine therapy for premenopausal women with ER+ breast cancer is tamoxifen for 5 to 10 years with or without LHRH agonists, and aromatase inhibitor with LHRH agonists for high risk cases. Endocrine therapy causes a variety of toxicities during the endocrine therapy. Little information is there about long term toxicity of endocrine therapy, which must be very important clinically.
Endocrine therapy for premenopausal women with ER positive breast cancer Premenopausal women with breast cancer may survive for a long period after primary treatment. Standard endocrine therapy for premenopausal women with ER+ breast cancer is tamoxifen for 5 to 10 years with or without LHRH agonists, and aromatase inhibitor with LHRH agonists for high risk cases. Endocrine therapy causes a variety of toxicities during the endocrine therapy. Little information is there about long term toxicity of endocrine therapy, which must be very important clinically.
Tamoxifen for 5 to 10 years as standard endocrine therapy for premenopausal women with ER+ breast cancer Tamoxifen 5 years vs, No ER positive disease only: entry age < 45 years 2614 women (44% node positive, 79% chemotherapy Tamoxifen 10 vs. 5 years EBCTCG. Lancet 378: 7771 784. 2011 Davies C et al., Lancet 381: 805 816, 2013
100 Tamoxifen or Exemestane with or without Ovarian function suppression in SOFT & TEXT trials Prior Chemotherapy Breast Cancer Free Interval 100 All women < 35 years of age Percent without Breast Cancer 80 60 40 20 0 0 T T+OFS E+OFS T T+OFS E+OFS Pts Events 5-yr % HR 95% CI 542 542 544 116 97 80 78.0 82.5 85.7.78.65.60-1.02.49-0.87 1 2 3 4 5 6 Years since Randomization Francis PA et al., N Engl J Med. 2015 Jan 29;372(5):436 46 Percent without Breast Cancer 80 60 40 20 0 0 T T+OFS E+OFS T T+OFS E+OFS Pts Events 5-yr % 95% CI 112 121 117 34 27 19 67.7 78.9 83.4 57.3-76.0 69.8-85.5 74.9-89.3 1 2 3 4 5 6 Years since Randomization 350 patients (11.5%) under age 35 94% received chemotherapy in this age group
Endocrine therapy for premenopausal women with ER positive breast cancer Premenopausal women with breast cancer may survive for a long period after primary treatment. Standard endocrine therapy for premenopausal women with ER+ breast cancer is tamoxifen for 5 to 10 years with or without LHRH agonists, and aromatase inhibitor with LHRH agonists for high risk cases. Endocrine therapy causes a variety of toxicities during the endocrine therapy. Little information is there about long term toxicity of endocrine therapy, which must be very important clinically.
Adverse events reported during treatment in SOFT trial Any event Tamoxifen (1,006) Tamoxifen + OS (1,005) Grade 3 or 4 Tamoxifen Tamoxifen + OS Hot flashes 79.8 93.4 7.6 13.2 Depression 46.6 51.9 3.8 4.4 Sweating 48.3 61.8 Insomnia 46.3 57.2 2.9 4.6 Hypertension 17.2 23.2 5.4 7.5 Musculoskeletal symptoms 69.0 75.1 6.3 5.5 Osteoporosis 12.3 20.0 0.1 0.3 Vaginal dryness 41.8 49.3 Decreased libido 42.4 47.5 Glucose intolerance 1.8 3.5 0.3 1.4 Any targeted adverse event 95.3 98.4 23.7 31.3 Francis PA et al., N Engl J Med. 2015 Jan 29;372(5):436 46
Treatment Effect: Hot Flushes in SOFT & TEXT trials QoL Score (Mean with 95% CI) No Chemo T Prior Chemo T No Chemo T+OFS Prior Chemo T+OFS QoL Evaluation Month Note: higher score indicate better condition Ribi K. San Antonio Breast Cancer Symposium 2014
Endocrine therapy for premenopausal women with ER positive breast cancer Premenopausal women with breast cancer may survive for a long period after primary treatment. Standard endocrine therapy for premenopausal women with ER+ breast cancer is tamoxifen for 5 to 10 years with or without LHRH agonists, and aromatase inhibitor with LHRH agonist for high risk cases. Endocrine therapy causes a variety of toxicities during the endocrine therapy. Little information is there about long term toxicity of endocrine therapy, which must be very important clinically.
Long term toxicities of endocrine therapy for premenopausal women Organs Role of estrogen Long term toxicities Brain Heart & Liver Ovary & Uterus & Vagina Bone Others Helps maintain body temperature Prevents memory loss Regulates cholesterol Reduces plaque build up in arteries Stimulates maturation Thickens vaginal lining Preserves bone mineral density Cognitive impairment Cerebrovascular disease Pulmonary embolism Fertility & Pregnancy Sexual functioning Bone health Second malignancies Uterus cancer
Cognitive impairment Neurocognitive symptoms ( onco or chemobrain ) are frequently described among young breast cancer survivors. Patient reported symptoms (forgetfulness, difficulty with concentration, fatigue, distractibility and difficulty with word findings) rarely correlate with neuro imaging studies and neuropsychiatric evaluation. While much of the prior work has focused on the effects of chemotherapy, endocrine therapy may also adversely affect cognition, although few specific investigations have been conducted and none in young women. Paluchi Simon S, et al., The Breast 26: 87 99, 2016
Bone health Premature menopause and/or treatment related amenorrhea increase the risk of bone thinning. Bone health should be checked regularly (similar to older women) in young women with breast cancer, especially in those receiving OFS plus oral endocrine therapy. Tamoxifen can cause bone loss in premenopausal patients, likely because it is a weaker agonist in the bones that the premenopausal endogenous estrogens it is blocking. Paluchi Simon S, et al., The Breast 26: 87 99, 2016
Fertility and sexual functioning Fertility and family planning are major concerns for young women with breast cancer. Premature menopause and/or treatment related amenorrhea lose the chance to have a pregnancy, as well as long term oral endocrine therapy for five or ten years. Sexual dysfunction is a major issue having significant impact on quality of life. This issue encompasses vaginal dryness, dyspareunia, decrease libido, body image concerns, anxiety and depression, fatigue and side effects from medications (including anti depressants). Paluchi Simon S, et al., The Breast 26: 87 99, 2016
EBCTCG meta analysis Mortality : 5 years tamoxifen vs. Not Entry age < 45, ER+ Lancet 378: 7771 784. 2011
Uterus (not cervix) cancer incidence: 5 years tamoxifen vs. Not < 45 y.o. 45 54 y.o. 55 69 y.o. Lancet 378: 7771 784. 2011
The long term effect of 2 years adjuvant tamoxifen compared with no systemic treatment was evaluated. 564 premenopausal patients with breast cancer were randomized, between 1984 and 1991. The median follow up for the 250 patients still alive in 2014 was 26.3 years (range, 22.7 to 29.7 years) No patients were lost to follow up (the Swedish Cause of Death Register) Ekholm M et al., J Clin Oncol 34: 2232 2238, 2016
The effect of 2 year tamoxifen on survival of premenopausal women with ER+ BC CM: cumulative mortality CBCM: cumulative breast cancer related mortality Ekholm M et al., J Clin Oncol 34: 2232 2238, 2016
Cause of death according to treatment arm Tamoxifen Control All 142 172 Breast cancer related 117 145 Other neoplastic disease 12 16 Arterial fibrillation 2 0 Myocardial infarction 4 0 Chronic ischemic heart disease 1 0 Sudden cardiac death 1 0 Cerebrovascular disease 1 1 Pulmonary embolism 0 0 Nonspecified or others 4 10 Ekholm M et al., J Clin Oncol 34: 2232 2238, 2016
Conclusions All premenopausal women should be counseled about the risks and associated symptoms and outcomes and management of treatment related toxicities before the onset of systemic therapy and informed of available ameliorative therapies. In order to improve the quality of life of premenopausal women with ER positive breast cancer, long term toxicity of endocrine therapy should be checked and managed as well as early side effects during treatment.