1. Mostafa AL Turk Tatiana Hawat

2. introduction

3. 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

4. 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

5. Methods

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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;

12. 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

13. Results

14. 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.

16. The end points

17. P value
0.01
0.007

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

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

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

21. 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

22. 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

23. 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)

24. 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

25. 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

26. 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

28. 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

30. 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)

31. 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

33. 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 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

34. 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.

35. 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.

36. 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

37. 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

38. 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

39. 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

40. Thank you for your attention
Mostafa AL Turk
Tatiana Hawat