Adjuvant Breast - Hormones

Question 1

What are the ways that you can suppress/ablate ovarian function?

Answer 1

1) Drugs
2) Radiotherapy
3) Oophrectomy

Question 2

What are the Aromatase Inhibitors that you know of?

Answer 2

1) 1st Generation (adrenal suppression)
- Aminogluthetimide
2) 2nd Generation
- Fadrozole
- Formestane
3) 3rd Generation (>98% inhibition)
- Steroidal (Irreversible) - Exemestane
- Non-steroidal (Reversible) - Anastrozole, Letrozole

Question 3

Define menopause

Answer 3

1) 60 years old and above

2) If

Question 4

Why is AI not appropriate as monotherapy for women with intact ovarian function?

Answer 4

AI only blocks peripheral conversion

May have return of ovarian function during f/u or may experience deactivation of ovarian function on an AI

Question 5

How does Tamoxifen work?

Answer 5

It is a SERM

Inhibits growth of breast cancer cells by competitive antagonism of Estrogen receptor

Question 6

What are the S/e of Tamoxifen?

Answer 6

Thromboembolic disease
Higher risk of CVA
Uterine cancer (4% vs 1%)
Hot flushes, vaginal discharge, sexual dysfunction, menstrual irregularities

Question 7

What contributes to Tamoxifen resistance?

Answer 7

1) Variable expression of ER alpha and beta isoforms
2) Intererence with binding of co-activators and co-repressors
3) Alternative splicing of ER mRNA variants
4) Modulators of ER expression
5) Inherited drug metabolizing CYP2D6 genotype

Question 8

What is the NCIC CTG MA.17 trial about

Answer 8

N>5000 post menopausal women s/p 5 years of Tamoxifen

2 groups:

1) Additional 5 years of Letrozole
2) Placebo

RESULTS:

• Improvement in DFS compared with placebo HR 0.5
• Improvement in OS HR0.6
• Women who had been randomized to placebo, but subsequently chose to take Letrozole also experienced an improvement in DFS despite a substantial lack in time.

Question 9

What are the side-effects of AI?

Answer 9

1) Osteoporosis and fractures
2) Cardiovascular risk
3) Hypercholestolemia
4) Lower risk of venous thrombosis and lower risk of endometrial cancer
5) MSK Symptoms
6) Fatigue, forgetfulness, insomnia
7) May reactivate ovarian function, esp in those with chemo-induced amenorrhea

Question 10

What are the AI-associated MSK Syndrome?

Answer 10

Arthralgia
Joint stiffness
Bone pain

Question 11

How do you manage AI-associated MSK Syndrome?

Answer 11

1) Exercise
2) NSAIDs
3) Alternate AI, after stopping for 2-8 weeks
4) Switch AI to Tamoxifen
5) Limited Tx with Duloxetine
6) HOPE trial (Hormones and Physical Exercise)
- n=120 post-menopausal women
- 2 arms: Exercise regimen vs usual care
» 2x per week supervised resistance and strength training + modest aerobic exercise for 150min/week
- 2013 San Antonio Breast Cancer symposium
» Significantly greater reduction in their worst pain score and severity
» More weight loss and improvement in exercise capacity

Question 12

When is the 21-gene RT-PCR Assay (Oncotype Dx) appropriate?

Answer 12

Node negative, Her2 negative

Tumor > 0.5cm

Question 13

Briefly describe the Oncotype Dx and how it correlates with treatment

Answer 13

Low recurrence score

Question 14

What is Oncotype Dx based upon?

Answer 14

Retrospective and not prospective.

It is prognostic and predictive, based on NSABP 14/20 and SWOG studies.

It is a RT PCR-based gene profiling assay
Based on 16 cancer genes and 5 reference genes

Gives a continuous variable, estimating a 10-year recurrence rate.
Risk: Low, Intermediate and high.
Based on the score, a recommendation of endocrine, endocrine+/-chemo, chemo will be suggested.

Patient profile:

• Stage I/II
• Node negative
• ER+

1/3 of the overall population switched from C+H to H, based on low recurrence score.
4% of overall population switched from H to C+H based on high recurrence score

Question 15

How did we come about to use CMF?

Answer 15

Milan Trial, Bonadona et al NEJM 1976, 19y update in NEJM 1995

N=400
S/p radical mastectomy. 2 arms:
1) Observation
2) Oral CMF Q4w X 12 (1 year)

Results (Updated):
Persistent RFS and OS benefit

Question 16

Btwn Oral and IV CMF. Which one?

Answer 16

Oral CMF > IV CMF
In both met and adjuvant setting

1) EORTC 10808 Eur J Cancer 1991
2) IBCSG JCO 1998

Question 17

What is the duration of CMF advised. Why?

Answer 17

6 months of oral CMF.

1)

Question 18

Btwn CMF and anthracyclines-based regimens?

Answer 18

1) INT 0102
- Oral CAF x6 > CMFx6 in terms of RFS and OS marginally
- n=4400, Node negative

2) NSABP B-15 JCO 1990
- 6 Oral CMF = 4AC = 4AC–>CMF

3) NSABP B-23 JCO 2001
- 6 Oral CMF = 4AC
- Node negative patients
- Tam = No Tam

4) GEICAM Ann Oncol 2003
- FAC > CMF for node-negative breast cancer
- OS same in Node+ patients

Question 19

Tell me about the INT-0102 trial

Answer 19

Hutchins JCO 2005

Aim:
to evaluate efficacy of CMF vs CAF in N- breast cancer;
With and without Tamoxifen

N=2700
Node negative, Tumor >2cm, HR - or high S-phase fraction

2x2 factorial design

1) CMF
2) CAF
3) CMF+Tam
4) CAF+Tam

RESULTS:
10y OS 85% (CAF) vs 82% (CMF)
10y DFS 77% (CAF) vs 75% (CMF) but not sig
Toxicity was greater with CAF, but did not increase with Tam.
Tam had no benefits In HR- patients

Question 20

Tell me about the NSABP B-23 trial

Answer 20

Bernard Fisher JCO 2001

N=2000
ER-, Axillary LN-

2x2 factorial design
1) CMF + Placebo
2) CMF + Tam
3) AC + Placebo
4) AC + Tam
Tam given daily for 5 years 
6# CMF and 4# AC 

RESULTS:

• No difference in RFS, EFS, or OS
• AC = CMF