Hormone therapy in

nonmetastatic carcinoma breast

DR SAILENDRASENIOR RESIDENT

DEPT OF RADIOTHERAPYMAULANA AZAD MEDICAL COLLEGE

IDEAL CANDIDATES FOR HORMONE THERAPY

POSITIVE

ERPR

menopauseWomen 60 years and olderPost bilateral oophorectomy.No menstrual periods for 12 months or more in the absence of tamoxifen, chemotherapy, or ovarian suppression and the serum estradiol is in the postmenopausal range.Amenorrheic on tamoxifen and follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal range.

FSH> 40 mIU/mlEstradiol < 30 pg/mlMENOPAUSE

•TVS•SERUM FSH AND ESTRADIOL •ROUTINE CARDIAC STATUS ASSESMENT

INVESTIGATIONS

Treatment options

SERMTAMOXIFEN

MECHANISM OF ACTION

TAMOXIFEN

DOSE 20mg once daily per oralCell cycle specific mid G1 phase

Side effects of tamoxifen• Deep vein thrombosis and pulmonary emboli• Stroke• Endometrial hyperplasia,polyp and carcinoma• Hot flushes • Vaginal discharge• Sexual dysfunction• Menstrual irregularities• Transient tumour flare• Fluid retention and peripheral edema

Mechanism of resistance

Decreased expression of ER Mutation in EROver expression of other growth factor receptors like EGFR,HER 2,IGFR etc

AROMATASE INHIBITORSANASTRAZOLE (1 mg daily) LETROZOLE (2.5 mg daily) EXEMESTANE (25 mg daily)

Side effects of AIMUSCULOSKELETAL SIDE EFFECTS • Carpal tunnel syndrome • AI-associated musculoskeletal syndrome (AIMSS), characterized by joint pain and stiffness• AIMSS is responsible for treatment discontinuation in 10 to 20 percent of patients  REACTIVATE OVARIAN FUNCTIONOSTEOPOROSIS CARDIOVASCULAR RISKHOT FLUSHESFATIGUEFORGETFULNESsSEXUAL DYSFUNCTION

AIMSS• A significantly greater reduction in worst pain score and pain severity occurs in patients doing regular physical exercise compared with usual care. TREATMENT• NSAIDS• DULOXETIN• DISCONTINUE AI

HOPE TRIAL,J Cancer Surviv. 2016 Aug;10(4):654-62

TAMOXIFENVENOUS THROMBOSISENDOMETRIAL CANCER

AROMATASE INHIBITORSOSTEOPOROSISFRACTURESCARDIOVASCULAR RISKHYPERCHOLESTEROLEMIA

TREATMENT APPROACHPREMENOPAUSAL

HIGH RISK

OVARIAN SUPPRESSION + AI

LOW RISK

TAMOXIFEN

POST MENOPAUSAL

AROMATASE INHIBITORS

HIGH RISK FEATURESPathologically involved lymph nodesLarge tumor sizeHigh tumor gradeLymphovascular invasionYounger age (i.e, age ≤35 years)

Suppression of Ovarian Function Trial (SOFT)Tamoxifen and Exemestane Trial (TEXT)

 ALL POSTMENOPAUSAL WOMEN WHO ARE CANDIDATES FOR ENDOCRINE THERAPY SHOULD BE OFFERED TREATMENT, REGARDLESS OF AGE.

SOFT TRIAL

N Engl J Med 2015;372:436-46

NO DIFFERENCE IN DFS AND FREEDOM FROM BREAST CANCER AT 5 YEARS

Exemestane plus Ovarian Suppression had a higher rate of Freedom From Breast Cancer

TAMOXIFEN AND EXEMESTANE TRIAL(TEXT)

• 2 ARMS• TRIPTORELIN + EXEMESTANE VS• TRIPTORELIN + TAMOXIFEN

• AUGUST 2003• PRIMARY COMPLETION DATE – JUNE 2014

COMBINED ANALYSIS• 4690 women were included in the intention to treat population• Median follow up period – 68months

N Engl J Med 2014;371:107-18

DFS IS BETTER WITH EXEMESTANE AFTER 5 YEARSNO DIFFERENCE IN OVERALL SURVIVAL

TREATMENT DISCONTINUE IS MORE WITH EXEMESTANE(16% Vs 11%)

EBCTCG METAANALYSIS

REDUCED BREAST CANCER RECURRENCE AND 1OYR MORTALITY WITH AROMATASE INHIBITOR5 years of Aromatase inhibitor versus 5 years of Tamoxifen

5 years of aromatase inhibitor versus tamoxifen to years 2–3 then aromatase inhibitor to year 5

•A trend towards reduced breast cancer mortality, which did not reach statistical significance•Lower recurrence in 0-1 yr

Tamoxifen to years 2–3 then aromatase inhibitor to year 5 versus 5 years of tamoxifen

Reduced recurrence as well as reduced 10yr breast cancer mortality

OBESRVATION

Highest risk for recurrence is within the first few years after initial diagnosis

Aromatase inhibition, is preferable to tamoxifen during that time

However, once patients have remained disease-free for a few years, switching to tamoxifen is similarly effective to continuation of AI treatment

Is there a preferred aromatase inhibitor?

All AIs appear to have similar efficacy in the adjuvant setting. Therefore, no one AI is preferred over another

Duration of endocrine treatment •  AI only 5yrs• AI to tamoxifen   5yrs• Tamoxifen to an AI 5-10 yrs• Tamoxifen only 10 years

•MA-17 TRIAL•NSABP B-33 TRIAL•ATLAS TRIAL•aTTom TRIAL

4 TRIALS PROVIDED INFORMATION

NCIC CTG MA.17 trial• over 5000 postmenopausal women who had completed a five-year course of  Tamoxifen were randomly assigned to treatment with an additional five-year course of letrozole or placebo.• Median follow-up period was 64 monthsLetrozole was associated with• Improvement in DFS compared with placebo (HR 0.52, 95% CI 0.45-0.61)• Improvement in OS (HR 0.61, 95% CI 0.52-0.71)• Interestingly, women who had been randomized to placebo and subsequently chose to take letrozole after the trial results were published still experienced an improvement in DFS, despite a substantial lapse in time between therapies (median, 2.8 years)

NSABP B-33 TRIAL• Suggested a benefit to exemestane over placebo after an initial five-year course of tamoxifen. • However, the trial was terminated early due to the positive results of the MA.17 trial.

RECURRENCE MORTALITY

Significant reduction in the risk of recurrence and breast cancer mortality with 10yr of tamoxifen compared with a five-year treatment course

Timing of endocrine therapy • For women with hormone receptor-positive breast cancer who are not recommended to receive other adjuvant therapy (eg, chemotherapy and/or radiotherapy), endocrine therapy is usually initiated four to six weeks after surgery.

WITH OR AFTER CHEMOTHERAPY

• North American Intergroup trial, 637 postmenopausal women with node-positive, hormone receptor-positive breast cancer were treated with chemotherapy and randomly assigned to treatment with tamoxifen initiated during or following completion of chemotherapy. • At 13 years of follow-up, sequential treatment resulted in:• A trend towards improvement in DFS compared with concurrent treatment (HR 0.84, 95% CI 0.70-1.01)• No improvement in OS (HR 0.90, 95% CI 0.73-1.10)

With or following radiation therapy

•  Multiple studies show that the timing of endocrine therapy in relation to RT does not impact survival• Some older studies suggest that concurrent treatment increases the risks of treatment complications (including pulmonary and/or breast fibrosis)

• Women of childbearing potential — Women who are of childbearing potential should be advised to use an effective means of contraception while on Tamoxifen  treatment because tamoxifen can induce ovulation.• Following completion of  Tamoxifen treatment, a waiting period of two months from drug discontinuation prior to attempting pregnancy is suggested to ensure that it has been cleared from the body

Pregnancy and tamoxifenTamoxifen use is contraindicated during pregnancy as it can cause congenital anomaly

summary• High-risk breast cancer - ovarian suppression plus exemestane • Low risk breast cancer - Tamoxifen  as single-agent therapy• As single-agent therapy, aromatase inhibitors (AIs) should not be used in women with intact ovarian function.• Postmenopausal women - aromatase inhibitor• For women who start on  Tamoxifen,switch to an AI within the first three years of treatment to complete at least five years of endocrine therapy

summary• For women treated with  Tamoxifen  for five years who are not candidates for an AI for whatever reason (including women who are not menopausal after tamoxifen and those who cannot tolerate an AI), we recommend extended treatment with tamoxifen for 10 rather than five• Women with childbearing potential should use an effective means of contraception while on  Tamoxifen. • Wait for 2-3 months before attempting pregnancy• Frequency of congenital anomalies associated with tamoxifen if taken during pregnancy.