6. ANDROGEN OESTROGEN
Thuốc ức chế aromatase (AI)
(như exemestane (Aromasin®))
Aromatase Thụ thể nội tiết
Đieàu trònoäi tieát nhoùm AIs
Thuốc điều hòa thụ thể
estrogen chọn lọc (như
tamoxifen)
Exemestanelà chất ức chế không thuận
nghịch, có cấu trúc giống chất nền tự nhiên của
aromatase là androstenedione
7. Lieäu phaùpnoäitieát boå trôï trong ung thö vuù
• Ñoái töôïng BN: Coù thuï theå noäi tieát (+)
• Ñaùp öùng toát (giaûm daàn)
• ER(+) vaø PR (+)
• ER (+)PR(-)
• ER (-) PR (+)
• ER (+++)ñaùp öùng toát hôn ER (+)
15. Phaântích goäp caùcnghieân cöùulaâmsaøng so saùnhAI vaø Tamoxifen
J. Ingle, M. Dowsett, J. Cuzick, C. Davies for the Aromatase Inhibitors Overview group (AIOG)
(JCO, 2010, in press)
16. Phaântích goäp caùcnghieân cöùulaâmsaøng so saùnhAI vaø Tam duøng ñôntrò, treân
tyû leä taùi phaùt
Đoàn hệ 1
9856 BN
17. Tyû leätöû vong doUT vuù,töû vong khoângtaùi phaùt vaø töû vong do baát kyø
nguyeân nhaân
Đoàn hệ 1
Không có sự khác biệt
18. Phaântích goäp caùcnghieân cöùulaâmsaøng so saùnhAI vaø Tam duøng chuyeånñoåi,
treântyû leä taùiphaùt
Đoàn hệ 2
9015 BN
19. Tyû leätöû vong doUT vuù,töû vong khoângtaùi phaùt,vaø töû vong do baát kyø
nguyeân nhaân
Đoàn hệ 2
20. ↓ thuyên tắc tĩnh mạch sâu
↓ ung thư nội mạc tử cung
↓ cơn nóng bừng mặt
↑ đau cơ/khớp
↑ nguy cơ loãng xương
Aromatase
Inhibitor
nguy cơ loãng xương
đau cơ
tăng mỡ máu
↑ cơn nóng bừng mặt
↑ thuyên tắc huyết khối
↑ ung thư nội mạc tử cung
↑ độc tính niệu dục
Löu yù taùc duïng phuïkhilöïa choïnnoäitieát
Tamoxifen
21. Postmenopausal women with
hormone receptor–positive
early breast cancer after
adequate
local treatment
(N = 7576)
Anastrozole 1 mg/day
(n = 3787)
5 yrs
Exemestane 25 mg/day
(n = 3789)
Stratified by lymph node status (positive/negative/unknown),
adjuvant chemotherapy (yes/no), trastuzumab use (yes/no
after 2005), celecoxib use* (yes/no; stopped in 2004), aspirin
use (yes/no; stopped in 2004)
Shepherd LE, et al. ASCO 2012. Abstract 501.
NC Phase III MA.27: Exemestanevs Anastrozole trong ung thö vuù giai ñoaïn
sôùm
• Muïc tieâu chính: EFS (khoâng gaëp) vaø di caên xa DFS
• EFS ñöôïc ñònhnghóa laø taùi phaùttaïi choã hoaëc di caên xa, ungthö vuù nguyeânphaùp môùi hoaëc
cheát do baát kyønguyeânnhaân
*In initial 2 x 2 randomization (n = 1622), patients in each arm also randomly assigned to celecoxib 400 mg BID vs
placebo for 3 yrs.
Celecoxib discontinued in 2004; high cardiac risk factors present in 58% of patients.
22. NC PhaseIII MA.27: Hieäuquaû
Không có sự khác biệt có ý nghĩa về EFS (thời gian sống không
biến cố) và OS (thời gian sống toàn bộ) giữa nhóm Exemestane
s/v nhóm anastrozole
23. Exemestane, n (%)
3.761 (100)
Anastrozole, n (%)
3.759 (100)
p
Nóng bừng mặt
Viêm đau khớp
Đau cơ
Xuất huyết âm đạo
2.051 (55)
253 (7)
649 (17)
40 (1)
2.101 (56)
231 (6)
606 (16)
61 (2)
0,24
0,32
0,19
0,04
ALT
AST
Bilirubin
Trứng cá
Rậm lông
53 (1)
47 (1)
59 (2)
12 (0)
36 (1)
23 (1)
19 (1)
24 (1)
3 (0)
11 (0)
0,001
0,001
<0,0001
0,04
<0,0001
Nhồi máu cơ tim
Tai biến mạch não
Rung nhĩ
Tăng triglycerid máu
Tăng cholesterol máu
38 (1)
32 (1)
72 (2)
80 (2)
577 (15)
32 (1)
38 (1)
46 (1)
124 (3)
665 (18)
0,56
0,47
0,02
0,002
0,01
Loãng xương
Gãy xương lâm sàng
Gãy xương bệnh lý
1.171 (31)
358 (10)
136 (4)
1.304 (35)
354 (9)
136 (4)
0,001
0,91
0,98
NC PhaseIII MA.27: Caùc taùcduïngphuï
28. NC TEXT vaø SOFT: So saùnh Tamoxifen hoaëcExemestane vôùi OFS
Tamoxifen 20 mg/day
+ OFS* (n = 1328)
Premenopausal
Patients with HR+ BC
≤ 12 wks after surgery
(N = 2672)
Stratified by trial, use of chemotherapy, nodal status
*OFS
TEXT: triptorelin 3.75 mg IM every
28 days for 6 mos, then optional
bilateral oophorectomy or irradiation
SOFT: choice of method
TEXT
Exemestane 25 mg/day
+ OFS* (n = 1014)
Tamoxifen 20 mg/day
Premenopausal
patients with HR+ BC
≤ 12 wks after surgery
(if no chemo) or
≤ 8 mos after chemo
(N = 3066)
SOFT
Tamoxifen + OFS*
(n = 2344)
Tamoxifen 20 mg/day
+ OFS* (n = 1016)
Exemestane + OFS*
(n = 2346)
Exemestane 25 mg/day
+ OFS* (n = 1332)
Joint Analysis
5 yrs
Pagani O, et al. ASCO 2014. Abstract LBA1.
29. 60% of first failures involved distant sites, including soft tissue, bone, and
viscera
Patients, n HR (95% CI) 5-Yr DFS, %
E +
OFS
T +
OFS
E +
OFS
T +
OFS
All Patients 2346 2344 91.1 87.3
Cohort
No chemotherapy, TEXT
No chemotherapy, SOFT
Chemotherapy, TEXT
Prior chemotherapy, SOFT
526
470
806
544
527
473
801
543
96.1
95.8
89.8
84.3
93.0
93.1
84.6
80.6
Lymph Node Status
Negative
Positive
1362
984
1350
994
95.1
85.6
91.6
81.4
Exemestanevôùi öùc cheáchöùcnaêng buoàng tröùng caûithieänDFS
Pagani O, et al. ASCO 2014. Abstract LBA1. Reprinted with permission.
100
80
60
40
20
0
0
Percent
Alive
and
Disease
Free
1 2 3 4 5 6
Yrs Since Randomization
Median follow-up: 5.7 yrs
Difference 3.8% at 5 yrs
Exemestane + OFS (n = 2346)
Tamoxifen + OFS (n = 2344)
E + OFS
T + OFS
Events
216
298
HR
0.72
95% CI
0.60-0.85
P Value
.0002
5-yr DFS
91.1%
87.3%
.25 .50 .72 1.0 2.0 4.0
Favors E + OFS Favors T + OFS
30. Keát quaû veà hieäuquaûcuûaNC TEXT vaø SOFT5 naêm
• Exemestane + OFS đã cải thiện tái phát so với tamoxifen + OFS trong nhóm bn đã nhận hóa trị
• Some patients have good prognosis with endocrine therapy alone
• Những bn lớn tuổi có khối bướu nhỏ
Outcome, % Exemestane + OFS
(n = 2346)
Tamoxifen + OFS
(n = 2344)
HR (95% CI) P Value
5-yr BCFI 92.8 88.8 0.66 (0.55-0.80) < .0001
5-yr DRFI 93.8 92.0 0.78 (0.62-0.97) .02
5-yr OS 95.9 96.9 1.14 (0.86-1.51) .37
Outcome, % (n/N) Exemestane + OFS Tamoxifen + OFS HR (95% CI)
5-yr BCFI
TEXT 91.5 (78/806) 86.0 (118/801) 0.64 (0.48-0.85)
SOFT 86.1 (72/544) 82.2 (90/543) 0.82 (0.60-1.12)
5-yr DFRI
TEXT 91.8 (69/806) 89.2 (88/801) 0.77 (0.56-1.06)
SOFT 88.0 (61/544) 84.6 (77/543) 0.81 (0.58-1.13)
Outcome, % (n/N) Exemestane + OFS Tamoxifen + OFS HR (95% CI)
5-yr BCFI
TEXT 97.6 (13/526) 94.6 (31/527) 0.41 (0.22-0.79)
SOFT 97.5 (12/470) 94.8 (23/473) 0.53 (0.26-1.06)
5-yr DFRI
TEXT 98.0 98.1 0.76 (0.32-1.79)
SOFT 99.3 98.6 0.52 (0.13-2.07)
Pagani O, et al. ASCO 2014. Abstract LBA1.
The above slide presents a generalised view covering both pre- and postmenopausal situations
6
20
BID, twice daily; DFS, disease-free survival; EFS, event-free survival.
For more information on this study, go to http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/501.aspx
BC, breast cancer; HR+, hormone receptor positive; IM, intramuscularly; OFS, ovarian function suppression.
Joyce O’Shaughnessy, MD:
The TEXT and SOFT trials were randomized open-label multicenter phase III trials undertaken to identify the optimal endocrine therapy in premenopausal patients with hormone receptor–positive breast cancer. Patients received either tamoxifen or exemestane, each combined with ovarian function suppression (OFS) therapy, or tamoxifen alone. It is important to point out here that OFS with triptorelin was started concurrently with chemotherapy in the TEXT trial, if chemotherapy was indicated in the adjuvant setting. So, the TEXT trial did not focus on a group of patients who still had documented ovarian function after completion of chemotherapy. Whereas in the SOFT trial, patients were enrolled within 8 months of finishing adjuvant chemotherapy, if indicated, and did have to have documented ovarian function (estradiol in the premenopausal range) prior to enrollment in the SOFT trial.
These data were the biggest news at ASCO and something that we need to grapple with in terms of how to integrate this in our practice, which underscores the global importance of this SOFT and TEXT data.
DFS, disease-free survival; E, exemestane; OFS, ovarian function suppression, T, tamoxifen.
Joyce O’Shaughnessy, MD:
The authors presented data from the groups that received either tamoxifen plus OFS or exemestane plus OFS; data from the SOFT trial for the group that received tamoxifen alone has not yet been presented. As shown in the Kaplan-Meier curve, there was a 3.8% absolute improvement in 5-year DFS for patients in the exemestane plus OFS arm compared with tamoxifen plus OFS, and a 2% improvement in distant DFS. Interestingly, the proportion of patients who were disease free was very similar between the 2 arms for the first 2 years of the study before diverging. We know that breast cancers that recur within the first 5 years are biologically more proliferative and more aggressive, and we have seen that aromatase inhibitors offer benefit vs tamoxifen in postmenopausal women at risk for early recurrence. So, aromatase inhibitors are probably most essential for those patients with aggressive disease. Whereas at least in the postmenopausal setting, if patients have more indolent grade I/II breast cancer, initiating treatment with tamoxifen and then switching over to an aromatase inhibitor is probably sufficient, and I think the same general concept is true here as well. I think these data emphasize that aromatase inhibitors are more beneficial than tamoxifen for aggressive disease regardless of menopausal status.
Regarding the chemotherapy and no chemotherapy comparison for SOFT and TEXT in the forest plot, the disease-free status results are a bit better in TEXT than in SOFT. Although the reason for this difference in unclear, the question here is: If we are going to use luteinizing hormone-releasing hormone (LHRH) agonist, do we use the TEXT protocol and start from Day 1? Although the difference of the 5.2% absolute improvement with the TEXT vs 3.7% improvement with SOFT should be interpreted cautiously, the TEXT trial data give me permission to do so. When we give chemotherapy, we are postponing for 4-6 months the most important therapy, which is endocrine therapy. This is particularly true in patients under 35 with very strong ovarian function. So I am actually very happy to see the TEXT data, including their use of a LHRH agonist in the young than 40 years of age and higher-risk population from Day 1.
BCFI, breast cancer-free interval; DRFI, distant recurrence-free interval; OFS, ovarian function suppression; OS, overall survival.
Joyce O’Shaughnessy, MD:
This slides looks at breast cancer–free interval (BCFI) and the distant recurrence–free interval (DRFI) as well as OS. The data for both BCFI and DRFI are significant, although there was no significant difference in survival, as we would expect at this early time point. Importantly, these data do not give an indication of the efficacy of tamoxifen with or without OFS, if tamoxifen is selected for treatment, because we do not have the full results of the SOFT trial yet. What this does support is that, in patients with more aggressive breast cancer, an LHRH agonist plus aromatase inhibitor is an important consideration. In my experience, I have certainly had the impression that patients with more aggressive disease and greater tumor burdens can recur quickly following chemotherapy while receiving single-agent adjuvant tamoxifen, so it is particularly in this population that I will be using a OFS—oophorectomy or LHRH agonist—with exemestane. It is also important to point out that with LHRH agonists in the very young, the pharmacokinetics are such that you may not always get full estradiol suppression. It is important that these younger patients come in monthly for their injections of LHRH agonist depot formulation to ensure complete suppression. For patients at very high risk for recurrence, bilateral salpingo-oophorectomy can be considered.
CNS, central nervous system; NR, not reported; OFS, ovarian function suppression.
Joyce O’Shaughnessy, MD:
This slide shows the toxicities related to these treatment approaches. It can be difficult for a young woman to undergo treatment with an LHRH agonist and an aromatase inhibitor or tamoxifen regarding depression, musculoskeletal, osteoporosis, and hot flashes. There are many adverse effects here, and this can be a very challenging issue for us in practice.
AI, aromatase inhibitor; BC, breast cancer; BCFI, breast cancer-free interval; DFS, disease-free survival; DRFI, distant recurrence-free interval; HR+, hormone receptor positive; OFS, ovarian function suppression; OS, overall survival.
Joyce O’Shaughnessy, MD:
These data validate what I do in clinical practice. When I have patient who is younger than 40 years of age who is receiving adjuvant chemotherapy, the chances are high that she is going to recover ovarian function. If I were to recommend an LHRH agonist to her, I would add the LHRH agonist up front. Based on these data, I will probably do that more often going forward, particularly for those younger than 40 years of age in whom chemotherapy does not necessarily suppress ovarian function.
If a premenopausal patient has clearly indolent disease, I would recommend an LHRH agonist and tamoxifen for up to 5 years. We also have the data from the ATLAS and ATTOM trial, suggesting that 10 years of tamoxifen is feasible and provides additional reduction in recurrence and mortality.[1,2] For certain patients, that may be preferable to undergoing oophorectomy, and then switching to an aromatase inhibitor, which is another option after 5 years of tamoxifen. It will depend on risk assessment and the age of the patient. The younger the patient and the lower the risk, the more she may experience long-term effects of oophorectomy such as cognitive dysfunction, cardiovascular disease, osteoporosis, or significant weight gain. There are many potential comorbidities associated with oophorectomy, particularly for women younger than 35 years of age, so this decision should be based on a very individualized assessment.
For patients with a more aggressive disease, grade III or highly proliferative disease, especially with a greater tumor burden, these data mean that an LHRH agonist or oophorectomy and an aromatase inhibitor will provide improvement in DFS. So I would use an LHRH agonist from the beginning and probably discuss with the patient oophorectomy and an aromatase inhibitor.
The bottom line is to be able to take a highly individualized approach to endocrine therapy, balancing the risk of the breast cancer recurring, the biology of the disease, and trying to balance the risk of dying of breast cancer with the risk of short-term and long-term morbidity.
Denise A. Yardley, MD:
For preserving ovarian function in younger patients, I think there has always been a question about whether to give an LHRH agonist up front prior to the initiation of chemotherapy or even concurrent with chemotherapy to preserve ovarian function and whether this would mitigate some of the chemotherapy benefits. Like you, Dr. O’Shaughnessy, I agree that these data suggest that I am not doing something harmful for these patients when I use LHRH agonists in this setting. Also, like you pointed out, it is important to monitor ovarian suppression while using LHRH agonists. In my own practice, I start with monthly injections of LHRH agonist, and then switch to the 3-month depot formulations once complete ovarian suppression is established by biochemical assays that measure estradiol levels because I worry about the ability of the longer-term depot formulation to achieve complete ovarian suppression at the outset. Once the patient is switched over to the 3-month formulation, it is important to continue to make sure they remain suppressed, particularly if using an aromatase inhibitor for those patients.
I have been using this strategy fairly exclusively for patients with high-risk ER-positive cancers, although now I have to think about the ER-negative patients who might also derive benefit, based on the next presentation on data from the phase III POEMS trial.[3] As I explain to patients, anything that offers a potential risk reduction short of oophorectomy is worth trying. I usually give them a trial of the LHRH agonist first to be sure that they are on board with the menopausal symptoms that accompany this strategy before I refer them for oophorectomy. I think there are many takes on this particular abstract that give us more security in what we have been doing for some of these patients without having a good body of data behind it.
Joyce O’Shaughnessy, MD:
I agree. I think there will be a lot of ongoing conversations about these new data. I think they have real practical importance.
References
Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805-816.
Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 in 6,953 women with early breast cancer. ASCO 2013. Abstract 5.
Moore HC, Unger JM, Phillips KA, et al. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). Program and abstracts of the 50th Annual Meeting of the American Society of Clinical Oncology; May 30 - June 3, 2014; Chicago, Illinois. Abstract LBA505.
