management of premenopausal hormonal receptor positive breast cancer

1. MANAGEMENT OF THE
PREMENOPAUSAL ER+VE BREAST
CANCER
Ahmed Allam Abdelhamed Mohamed
MBChB,MSc.
Assistant Lecturer of Clinical Oncology
Assiut University Hospitals

2. Quick Facts
• Approximately 25% of all breast cancers occur in women
aged younger than 50 years.*
• Estrogen plays a key role in mammary carcinogenesis
• Studies of endocrine manipulation conducted in advanced
breast cancer have revealed response rates of 80% for
ER+/PR+ tumors, 40–45% for ER–/PR+ tumors, 25–30%
for ER+/PR– tumors, and less than 10% for ER–/PR
tumors.**
• The over-expression of ER or PR in at least 1% of breast
tumor cells indicates potential responsiveness to
endocrine therapy
* SEER
** Harvey J, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine
therapy in breast cancer. J Clin Oncol. 1999;17:1474–81
.

3. Estrogen Production in Premenopause

4. Peripheral production of Estrogen
Adrenal Hormones
Cortisol Androstenedione Aldosterone
Estrone Testosterone
Estradiol

5. Estrogen and Breast Cancer
Aromatase SERMS, SERDS
inhibitors, ovarian
suppression
Estrogen
Cell
Growth
and
Division
Estrogen
Receptor

6. Endocrine Therapy in Breast Cancer
• Selective Estrogen Receptor Modulators
• tamoxifen
• toremifene
• raloxifene
• Aromatase inhibitors
• anastrozole
• letrozole
• exemestane
• Medical or surgical oophorectomy (premenopausal)
• Selective Estrogen Receptor Downregulators
• fulvestrant
• Others: Progestins, Estrogens, Androgens

7. Tamoxfine ,,, any evidence ?

8. EBCTCG 2000 , 2011 (Oxford Overview)
Tamoxifen 5 years vs. Nil: Disease-free Survival
ER Negative ER Positive
tamoxifen
nil
5 years of adjuvant
tamoxifen became
standard in ER+ patients
ER status matters!!
5 yrs
15 yrs

9. Extending Adjuvant Tamoxifen.
aTTom: 5 years tamoxifen Vs 10 years
tamoxifen = risk of reccurrence was 28%
vs 32% and a significant 25% reduction in
the risk of breast cancer mortality starting
at year 10 (p = 0.007) among the 6,953
women enrolled in the trial
ATLAS:The risk for recurrence by year 15
was 21.4% in the continuers group and
25.1% in the control group.
In addition, breast cancer mortality by year
15 was significantly reduced by nearly 3%;
it was 12.2% in the continuers group and
15.0% in the control group.

10. Ovarian Suppression.
• Reversible: Pharmacologic: (LHRH) agonists such as
goserelin, deslorelin, and leuprolide.
• Reversible / Irreversible: RTH can also be offered as a
means of OS. A fraction of 450 cGy or 5/6 fractions
totaling 10 to 20 Gy have been effective; however, results
are often incomplete and normal ovarian function can
return in an unpredictable fashion. Chemotherapy is
known to suppress ovarian function, but the effects are
also unpredictable and can be either reversible or
irreversible
• Irreversible: oophorectomy: permanent and definitive.

11. OS alone
• Data from the 2005 EBCTCG Oxford Overview demonstrated the benefit of
OS alone in the treatment of premenopausal ER+ breast cancer
- Unfortunately, there were no data on the combination of OS with tamoxifen in
this analysis

12. OS + TAM Vs Chemotherapy.
• In the ABCSG Trial 5, 1,034 premenopausal patients with
ER+ disease were randomly assigned to OS with
goserelin for 3 years + TAM for 5 years or chemotherapy
(CMF for six cycles). At a median follow-up of 60 months,
the endocrine arm fared better with regard to DFS (81%
vs. 76%).
• The French Adjuvant Study Group Trial 06 randomly
assigned 333 premenopausal women with ER+ breast
cancer to treatment with OS with triptorelin + TAM for 3
years or chemotherapy (FEC for six cycles). The 7-year
DFS was 76% with endocrine therapy and 72% with
chemotherapy

13. ?

14. OS + TAM + Chemotherapy.
N Recurrence Recurrence
or death
Death after
recurrence
Chemo+Tam+
/- LHRH
Age < 40 81 31.1% (p=
0.31)
31.1%
(p=0.31
21.1 (p=0.66)
Age >40 284 5.3% 7.1% 23.4%
Lancet, 2007

15. Aromtase Inhibation.
• The AIs have shown small but significant improvements
compared with tamoxifen when given to postmenopausal
women in the adjuvant setting.*
Howell et al. Lancet 2005, Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast
cancer.

16. Aromtase Inhibation.
• They are contraindicated in premenopausal women since
the inhibition of aromatase results in negative feedback to
the hypothalamus with consequent ovarian stimulation

17. AIs + OS
• ABCSG-12: four-arm trial that assigned 1,803
premenopausal women with stage I or II ER+ breast
cancer previously treated with surgery to receive
goserelin plus tamoxifen or anastrozole for 3 years, with
or without zoledronic acid.
• At a median follow-up of 62 months, there was no
difference in DFS between patients receiving anastrozole
and tamoxifen, but overall survival was worse with
anastrozole compared with tamoxifen.

18. Ongoing trails on OS+AIs
• SOFT is a three-arm trial in which patients are randomly
assigned to tamoxifen alone, tamoxifen with OS, or AI
(exemestane) with OS.
• TEXT is a two-arm trial in which patients are randomly
assigned to OS (via triptorelin) with tamoxifen or OS with
an AI (exemestane).

19. Standard ???

21. “Self-education is, I firmly believe, the only kind of education
there is.”
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Isaac Asimov, American author and professor of biochemistry