MANAGEMENT OF THE

PREMENOPAUSAL ER+VE BREAST

CANCER

Ahmed Allam Abdelhamed Mohamed

MBChB,MSc.

Assistant Lecturer of Clinical Oncology

Assiut University Hospitals

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

.

Estrogen Production in Premenopause

Peripheral production of Estrogen

Adrenal Hormones

Cortisol Androstenedione Aldosterone

Estradiol

TestosteroneEstrone

Estrogen and Breast Cancer

Estrogen

Cell

Growth

and

Division

Estrogen

Receptor

SERMS, SERDSAromatase

inhibitors, ovarian

suppression

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

Tamoxfine ,,, any evidence ?

EBCTCG 2000 , 2011 (Oxford Overview)

Tamoxifen 5 years vs. Nil: Disease-free Survival

ER Negative ER Positive

5 years of adjuvant

tamoxifen became

standard in ER+ patients

tamoxifen

nil

ER status matters!!

5 yrs

15 yrs

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.

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.

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

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

?

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

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.

Aromtase Inhibation.

• They are contraindicated in premenopausal women since

the inhibition of aromatase results in negative feedback to

the hypothalamus with consequent ovarian stimulation

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.

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).

Standard ???

“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