Medical Management of Breast Cancer in Premenopausal Women

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Medical Management of Breast Cancer in
Premenopausal Women

• Dr Prue Francis
• Head of Breast Medical Oncology
• Peter MacCallum Cancer Centre

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Pathology Information Required for Optimal
Systemic Therapy Decisions

• Size tumour (invasive component)
• Grade tumour
• Presence of lymphovascular invasion (LVI)
• Lymph node involvement (no. of positive nodes)
• NB negative sentinel node maybe false negative

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Pathology Information Required for Optimal
Systemic Therapy Decisions

• ER cells positive and intensity of staining
• PR cells positive and intensity of staining
• ER/PR results on Core Biopsy maybe more
  accurate. RMH study 9 tumours assessed as
  receptor negative on surgical sample had positive
  hormone receptors when assessed on core biopsy.

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Pathology Information Required for Optimal
Systemic Therapy Decisions

• HER2 testing best done on surgical sample
  unless large tumour planned for neoadjuvant Rx
• Also request CISH or SISH testing (HER2 testing
  by IHC 6 IHC 1 are HER2 amplified while only
  80 of IHC 3 are amplified)

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Premenopausal Early Breast CancerAdjuvant
Systemic Therapy Decisions

• (1) Chemotherapy
• (2) Hormonal Therapy (for ER or PR positive)
• (3) Biologic Therapy (for HER2 positive)

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Premenopausal Early Breast Cancer Adjuvant
Systemic Therapy Decisions

• Have a low threshold for offering some
• form of adjuvant systemic therapy

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Tumour Size and Recurrence-Free Survival in Node
Negative Breast Cancer With No Adjuvant Treatment
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Premenopausal Early Breast Cancer Adjuvant
Systemic Therapy Decisions

• Adjuvantonline.com (available on internet)
• Enter data on patient age, health, tumor size and
  grade, ER status, lymph node involvement
• Gives 10 year prediction of risk of recurrence
  and death according to systemic treatments
  chosen
• (i) none
• (ii) hormone (eg tamoxifen, AI, tamoxifen?AI)
• (iii) chemotherapy (of various intensities)
• (iv) chemotherapy hormone

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Premenopausal Early Breast CancerAdjuvant
Systemic Therapy Decisions

• Adjuvantonline.com imperfect tool
• Cant enter how strongly positive the ER is
• Doesnt include the PR status
• Does not yet include HER2 status/Rx
• Cant enter actual tumour size and nodal status
  only a range ( ie. 1-3 nodes)

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Premenopausal Early Breast CancerAdjuvant
Systemic Therapy Decisions Whats New?

• Oncotype DX Assay
• Suitable for node negative ER/PR positive tumors
• Commercial assay based on 21 genes (not funded)
• Patient has to pay 3000 - tumour sample sent
  to USA
• Recurrence Score (RS) correlates with a
  numerical risk of distant metastases at 10 yrs if
  treated with tamoxifen if low RS may avoid
  chemotherapy. High RS should get chemotherapy

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Oncotype DX
Multi-gene RT-PCR Assay for Predicting Recurrence
in Node Negative Breast Cancer Patients - NSABP
B-14 Study.
Results
Recurrence Score as a Continuous Predictor
Low RS lt 18 Rec. Rate 6.8 C.I. 4.0 - 9.6
Intermediate RS 18 - 31 Rec. Rate 14.3 C.I.
8.3 - 20.3
High RS ? 31 Rec. Rate 30.5 C.I. 23.6 -
37.4
Paik .S. et al. 26th annual San Antonio breast
cancer symposium 2004.
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Premenopausal Early Breast CancerAdjuvant
Systemic Therapy Decisions

• Chemotherapy
• consider in all Hormone Receptor negative tumours
• (ER negative and PR negative)
• consider in all HER2 positive tumours
• consider in all Node Positive tumours
• Benefit when added (prior) to tamoxifen in
  hormone receptor positive tumours

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Premenopausal Early Breast CancerAdjuvant
Chemotherapy

• Adjuvantonline describes 1st, 2nd and 3rd
  generation regimens
• later generation regimens often more toxic but
  more effective (used in patients at higher risk)
• 1st generation eg. AC x 4 or CMF x 6
• 2nd generation eg. FEC 100 x 6 or TC x 4
• 3rd generation eg. FEC x 3 ? T x 3 etc

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Adjuvant Chemotherapy vs None in Women lt 50 yrs

• Absolute Difference in Relapse Rates
• at 15 years (EBCTCG Overview data)
• Node Negative Breast Cancer 10
• Node Positive Breast Cancer 13

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Premenopausal Early Breast CancerAdjuvant
Chemotherapy- Late Toxicities

• Premature menopause
• Cardiac toxicity (with anthracyclines, herceptin)
• Leukemia (AC or FEC but not CMF)
• Peripheral Neuropathy (paclitaxel gt docetaxel)

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Premenopausal Early Breast CancerAdjuvant
Hormonal Therapy

• Tamoxifen standard therapy for all ER or PR ve
• Benefit when added to chemotherapy
• 5 years tamoxifen more effective than 2 years.
• ? 10 years better than 5 years in premenopausal
  women await publication of ATLAS trial
• Women (especially those not tolerating well) need
  to know that it makes a big difference

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Benefit from 5 years of Adjuvant Tamoxifen vs
none in ERve Breast Cancer (EBCTCG data)
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Premenopausal Early Breast CancerAdjuvant
Hormonal Therapy

• Tamoxifen
• Previously used as a fertility treatment
• Women on tamoxifen may not menstruate but still
  be fertile
• May harm a developing fetus
• Discuss the need for non-hormonal contraception
• Cease pre/post-operatively re risk thrombosis

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Premenopausal Early Breast CancerAdjuvant
Hormonal Therapy

• Aromatase Inhibitors (AI)
• Effectiveness in women lt 45 years who seem
  postmenopausal after chemotherapy is uncertain
  (unless ovaries removed). BEWARE..
• AI GnRH injections (to suppress ovaries) being
  tested in trials eg SOFT and TEXT

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Premenopausal Early Breast CancerAdjuvant
Hormonal Therapy

• GnRH Analogues (eg goserelin zoladex, and
  triptorelin)
• Given by injection every 4 weeks
• Reversible form of ovarian function suppression
  (makes women temporarily postmenopausal)
• TGA approved but not PBS reimbursed
• Sometimes used as alternative to chemotherapy
• Benefit after chemotherapy uncertain (SOFT)

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Premenopausal Hormone Receptor Positive Breast
Cancer Adjuvant Therapy

• Chemotherapy effective
• Tamoxifen effective
• Ovarian ablation/suppression effective
• Women lt 35 years worse outcomes if ER or PR ve
• Important Questions Remain
• Are all three treatments required in very young
  women?
• Are aromatase inhibitors superior to tamoxifen in
  premenopausal women if suppress ovarian function?

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SOFT (Suppression of Ovarian Function
Trial) IBCSG 24-02 Premenopausal Trial
Stratification
Treatments
Tamoxifen for 5 years
R A N D O M I S A T I O N
Institution Prior chemotherapy (no/yes) Number
of positive lymph nodes (0 1) Intended method
of OFS (GnRH analogue for 5 yrs oophorectomy
ovarian irradiation)
SURGERY
OFS plus Tamoxifen for 5 years
OFS plus Exemestane for 5 years
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Premenopausal Early Breast CancerAdjuvant
Hormonal Therapy

• Ovarian ablation (oophorectomy) is an effective
  adjuvant treatment for hormone receptor positive
  tumours
• Oophorectomy/ Ovarian suppression tamoxifen
  maybe used instead of chemotherapy in node
  negative low risk tumours with strongly positive
  ER and PR
• Salpingo-oophorectomy maybe chosen in BRCA gene
  carriers for reducing risk of current ER ve
  breast cancer and risk of future new breast and
  ovarian cancer

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Premenopausal Early Breast CancerBiologic
Therapy

• Trastuzumab (Herceptin)
• For HER2 positive tumours give concurrently
  with taxane chemotherapy and continue for 12
  months with heart monitoring every 3 months
• Regimens
• AC ?taxane herceptin (15 mths to complete)
• TCH x 6 docetaxel carboplatin herceptin
• (12 mths)
• ? Consider infusaport if 2nd surgery required

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Disease-Free Survival
AC?TH
87
85
AC?T
75

67
N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
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B-31/N9831 Survival
AC?TH
94
91
AC?T
92
87
N Deaths AC?T 1679 92 AC?TH 1672 62
HR0.67, 2P0.015
Years From Randomization
B31/N9831
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Premenopausal Early Breast CancerBiologic
Therapy

• Current Adjuvant Trials for HER2 ve pts
  receiving adjuvant chemotherapy
• ALTTO compares herceptin, lapatinib or
  combination
• BETH comparing herceptin/- bevacizumab
  (avastin)

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Premenopausal Early Breast CancerBiologic
Therapy

• Bevacizumab (Avastin)
• Currently being tested in adjuvant trials
• BETH HER2 positive tumours
• BEATRICE Triple Negative tumours ie. ER
  negative, PR negative, HER2 negative)

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Premenopausal Early Breast CancerFertility
Considerations

• Chemotherapy may cause menopause or reduced
  ovarian reserve
• Delaying pregnancy for 5 years of hormonal
  therapy will reduce fertility
• Fertility after breast cancer treatment is age
  and regimen dependent

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Risk of Menopause During the First Year After
Breast Cancer Diagnosis CMF or CEF
Goodwin et al JCO 172365, 1999
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Risk of Menopause After Adjuvant Chemotherapy

• Varies according to chemotherapy regimen
• Classic CMF (6 months) ? 69 become menopausal
• AC x 4 (3 months) ? 34 become menopausal

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STRATEGIES TO PRESERVE FERTILITY

• ovarian protection during chemo
• gamete, ovarian tissue and embryo storage prior
  to chemotherapy
• use of donor oocytes if necessary

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CRYOPRESERVATION

• mature oocytes
• embryos
• ovarian tissue

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AUTOGRAFTINGThe Lancet Oct 2004

• Livebirth after orthotopic transplantation of
  cryopreserved ovarian tissue
• J Donnez, M M Dolmans, D Demylle, P Jadoul, C
  Pirard, J Squifflet, B Martinez-Madrid, A Van
  Langendonckt
• Lancet 2004 364 1405-10

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SWOG 0230/ IBCSG 34 POEMS Phase III Trial of
Zoladex during Chemotherapy to Reduce Ovarian
Failure after Standard Adjuvant Chemotherapy in
Hormone Receptor Negative Breast Cancer
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STUDY SCHEMA

STRATIFY
Zoladex standard chemo

• lt50 yo
• premenopausal
• Stage I, II, IIIA
• HR negative
• Adjuvant cyclophosphamide containing chemo
  planned

• age
• lt40 vs gt40
• chemo type

RANDOMISE
Standard chemo alone
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POEMS (IBCSG 34) Trial Rationale

• No advantage to premature ovarian failure in this
  hormone receptor negative subgroup
• Disadvantages hot flushes, genitourinary/sexual
  dysfunction, mood changes, accelerated
  osteoporosis, infertility

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POEMS (IBCSG 34) Trial Rationale

• Suppression of the pituitary-gonadal axis may
  help to preserve ovarian follicles and germinal
  epithelium from toxic effects of chemotherapy
• Several small Phase II studies have examined the
  role of GnRH agonists (Zoladex) as gonadal
  chemoprotectants
• (Blumenfeld 1999, Damewood 1986, Waxman 1987,
  Recchia 2002)

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Pregnancy After Early Breast Cancer

• No evidence that it increases risk of recurrence
• Problem of how to treat if relapse occurs during
  pregnancy
• If cancer relapses later, child likely to
  experience death of mother at young age
• Relapses can occur between 5-10 years (especially
  in hormone receptor positive tumours)

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Early Breast Cancer

• The Good News
• Majority cured with optimal therapy

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The statistics are compelling
Breast Cancer Deaths