Mostafa AL Turk Tatiana Hawat

introduction

The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two Tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years 3) These treatments are administered in a variety of adjuvant regimens, including

This trial examined the effects of treatment with an aromatase inhibitor for 10 years rather than just 5 years after any duration of prior treatment with tamoxifen

Methods

Study Design It was a randomized, double-blind, placebo-controlled trial Involving postmenopausal women with primary breast cancer Patients had received 4.5 to 6 years of adjuvant therapy with an aromatase inhibitor, preceded by treatment with tamoxifen

The Participants 1918 women were enrolled within 2 years after completing treatment with the aromatase inhibitor The patients were randomly assigned to receive 2.5 mg of letrozole or placebo orally once a day for 5 years Participants were stratified according to Lymph node status Prior receipt of adjuvant chemotherapy The interval between the last dose of aromatase inhibitor and randomization The duration of prior receipt of tamoxifen

Oversight The trial drug, letrozole, and funding support were provided by Novartis Novartis did not contribute to the accrual, analysis, or interpretation of the data or to the writing of the manuscript

Assessments Patients received annual clinical evaluations, which included new bone fractures new-onset osteoporosis routine blood work mammography drug toxic effects Assessment of And assessment of

Assessments Bone mineral density was measured by means of DEXA scan obtained within 12 months after study entry every 2 years thereafter at the completion of treatment Treatment was discontinued if there was a serious intercurrent illness, unacceptable toxic effects, or disease recurrence

Trail End Points The primary end point was disease-free survival Secondary end points included overall survival, the incidence of contralateral breast cancer, quality of life, and long-term safety which was defined as the time from randomization to recurrence of breast cancer (in the breast or chest wall or at nodal or metastatic sites) or the development of a new primary breast cancer The occurrence of a second type of cancer or death without breast cancer recurrence were not included as events in the analysis of disease-free survival;

Statistical Analysis For the study to have 80% power, at a two-sided 0.05 level, 196 events would need to be observed in order to see a difference But only 176 events had been observed by 6 years This constituted some power loss of the study

Results

The median time between the initial diagnosis of breast cancer and randomization was 10.6 years (interquartile range, 7.6 to 11.5). The median duration of prior treatment with tamoxifen was 5 years, with 68.5% of patients having received tamoxifen for 4.5 to 5.5 years and 20.7% having received no tamoxifen. The median duration of prior treatment with an aromatase inhibitor was 5 years, with 95.4% having received 4.5 to 5.5 years of treatment.

The end points

P value 0.01 0.007

Figure 1. Cumulative Incidence of Contralateral Breast Cancer P=0.007 Figure 1. Cumulative Incidence of Contralateral Breast Cancer

Figure 2. Kaplan–Meier Curves for Disease-free and Overall Survival

Figure 2. Kaplan–Meier Curves for Disease-free and Overall Survival

Safety The incidence of toxic effects was similar in both groups Bone related toxic effect were more common in Letrozole group 5.4% of patients in Letrozole group and 3.7% in Placebo group discontinued treatment due to adverse effects

Safety- Bone density Patient receiving Letrozole had a mean loss of bone mineral density in the total hip (-3.2%) and an increase 1.4% in the lumbar spine after discontinuation VS Increase in bone mineral density in hip (22.4%) and spine (4.5%) in patient receiving Placebo Group difference in the mean change in bone mineral density (p<0.001) was significant and favors Placebo Greater number of Letrozole patients had a T score at lumbar spine < -2.5 at any time after baseline

Safety A similar percentage of patients in the two groups used bone protecting medications: Ca supplements (86.1%) Vit D supplements (84.5%) SERM selective estrogen receptor modulator 0.3% Bisphosphonates (46.2% in L grp and 46.6% in P group)

Safety 133 patients receiving Letrozole who had a fracture: 56% were taking bisphosphonates 90% were taking Ca supplements 86% were taking a vitamin D supplement 88 patients receiving Placebo who had a fracture: 55% were taking bisphosphonates 86% were taking Ca supplement 88% were taking VitD supplement

Adverse events Event Letrozole (N = 959) Placebo (N = 954) P Value   Event Letrozole (N = 959) Placebo (N = 954) P Value number (percent) Toxic effect during receipt of trial regimen Edema 158 (16) 136 (14) 0.19 Hypertension 157 (16) 145 (15) 0.48 Hot flashes 360 (38) 354 (37) 0.84 Fatigue 346 (36) 355 0.61 Constipation 117 (12) 140 0.10 Diarrhea 105 (11) 81 (8) 0.07 Arthritis 317 (33) 288 (30) 0.18 Hypercholesterolemia 203 (21) 184 (19) 0.31 Dizziness 145 (15) 139 0.74 Headache 151 (16) 138 0.43 Insomnia 269 (28) 243 (25) 0.20 Arthralgia 513 (53) 475 (50) Myalgia 268 (28) 240 Bone pain 174 (18) 133 0.01

Event Letrozole (N = 959) Placebo (N = 954) P Value number (percent)   Letrozole (N = 959) Placebo (N = 954) P Value number (percent) Toxic effect during receipt of trial regimen Bone pain   174 (18) 133 (14) 0.01 Dyspnea 148 (15) 165 (17) 0.27 Vaginal dryness 102 (11) 96 (10) 0.68 Elevated alkaline phosphatase level — no./total no. (%)† 111/928 (12) 78/916 (9) Elevated aspartate aminotransferase level — no./total no. (%)† 133/928 (14) 131/915 (14) 0.92 Elevated alanine aminotransferase level — no./total no. (%)† 97/909 (11) 128/894 (14) 0.02 Bone fracture‡ 88 (9) 0.001 Spine 17 (2) 9 (1) 0.12 Wrist 27 (3) 16 0.09 Pelvis 1 (<1) 7 0.08 Hip 6 0.79 Femur 4 0.17 Tibia 5 0.74 Ankle 19 11 0.14 Other 68 (7) 48 (5) 0.06 New-onset osteoporosis 109 (11) 54 (6) <0.001 Cardiovascular event 116 (12) 98 0.21

Quality of Life > 85% completed the QOL assessment No significant change seen in the SF36 summary score SF- 36 short form heath survey, patient reported, consisting of 8 scaled scores (0-100). The lower the score, the more the disability. 8 sections: Vitality Physical funtioning Body pain General health perception Physical role Emotional role functioning Social role functioning Mental health

Quality of Life- SF36 Role physical subscale : worse prognosis were greater in Letrozole than in Placebo Body pain was greater in Letrozole at 12, 24, 36 mo but lower at 48 and 60 mo Single time points comparison showed no great significance (p= 0.07) Role emotional subscale, Letrozole had better score at month 12, 36, 60 but their scores were worse at 24 and 48 month Single time point comparison showed only major difference at 60 mo in favor of Letrozole (p=0.01)

Quality of Life- MENqol Menopause specific quality of life 4 subtypes: vasomotor, psychosocial, sexual, physical No significant differences between 2 groups seen in this questionnaire

Discussion MA.17R trial explored the effect of extending adjuvant treatment with an aromatase inhibitor beyond 5 years in women with early breast Ca. Treatment with an aromatase inhibitor for an additional 5 years after initial treatment of 4.5-6 years was beneficial in preventing disease recurrence independent of: nodal status prior adjuvant chemotherapy time since the last dose of aromatase inhibitor duration of prior therapy with tamoxifen or AI

Discussion The risk of disease recurrence and diagnosis of contralateral breast Ca was lower by 34% in women who continued aromatase inhibitor for 10 years than women who took placebo after 5 years AI. No overall difference in survival was noted at a median followup of 6.3 years.

Discussion For patients receiving treatment with Tamoxifen first, extension of Tamoxifen or AI for 10 years has been shown beneficial in reducing risk of recurrence. Most postmenopausal patients with HR+ early Ca now receive 5 years of treatment with AI as upfront therapy. It is was previously unclear for these patients if AI beyond 5 years is beneficial.

Discussion Greater percentage of women taking Letrozole had new onset osteoporosis and more clinical fractures (at osteoporotic site of proximal femur, thoracic/lumbar vertebra, wrist, proximal humerus..) ↑ in bone mineral density in patients receiving placebo. Minority of fractures in both groups were located at hip, spine, pelvis or femur. No significant changes in physical health recorded in either group perhaps because both women took protecting supplements

Discussion Low incidence of reported toxic effects => self-selection on part of the study participants who had few side effects throughout the first 5 years Were willing to undergo another 5 years of treatment

Main points Our study shows that it is safe and beneficial for postmenopausal women with HR+ breast Ca to take an AI as adjuvant therapy for 5 years after initial treatment. Higher rates of disease free survival and lower incidence of contralateral breast Ca with Letrozole But the rate of overall survival was not higher with AI than with placebo No significant differences in terms of QOL Validity of the adherence data is limited since we are based on self report

In the end The decision of whether a patient should receive prolonged therapy with an AI will depend on: extent of toxic effects QOL Maintenance of bone mineral density (indicated by sequential scans) Patient individual risk of disease recurrence

Thank you for your attention Mostafa AL Turk Tatiana Hawat