Dr. Lohrisch's research presentation is about a multi-disciplinary approach to treatment therapies that will assist oncologists in choosing the right treatment, for the right woman, for the right disease. Learn more about her research http://ow.ly/Fzfdt

1. Adjuvant systemic
therapy
Breast cancer

2. Survival after early breast
cancer
Improvements over time:
adjuvant taxanes, AIs (2000+)
Adjuvant trastuzumab (2005+)
Survival in BC: Best in Canada and similar to Australia, Sweden

3. Stage distribution at
presentation
Stage Definition % Patients
I T1N0 30
IIA T0N1
T1N1
T2N0
50
IIB T2N1
T3N0
IIIA T0N2
T1N2
T2N2
15
IIIB T4Nany
IIIC TanyN3
IV TanyNanyM1 5

4. Early BC treatment pples
 Surgery: PM, M, AXND, SNB
 Radiation: Breast, loco-reg, chest wall
 Hormone Rx: what, how long, who
 Chemotherapy: what, how much, who
 Anti-HER2 therapy: who, how long

5. Local Therapy
SURGERY
 Breast:
 Partial mastectomy
 Mastectomy
 Axilla:
 Sentinel node biopsy
 Most cases
 Axillary dissection
 May follow sentinel bx
 In clinically positive
nodes
RADIATION
 Breast:
 After partial
mastectomy
 After mastectomy if
 Positive surgical
margins
 Lymphatic invasion
 If positive nodes
 Nodes: if contain
cancer
 Axilla, supraclavicular,
internal mammary

6. Systemic Therapy
Choice of treatment is based on
 Hormone therapy: expression of ER, PR
 Chemotherapy: absolute recurrence risk,
age, co-morbidity
 Anti-HER2 therapy: HER2 positivity,
indications for chemotherapy, adequate
cardiac function

7. How to Assess risk and
treatment benefit
 Traditional: T, N, grade, ER, HER2,
LVI
 Enhanced pathology: Adjuvant! On
line (adds age, co-morbidity, effect
of adjuvant intervention)
 Other prognostic tools: Oncotype
Dx, mammaprint, PAM50, etc

8. The old paradigm
High risk: chemo
 Young
 Node positive
 Big cancer
 High grade
 ER –
 HER2+
Low risk: no chemo
 Older
 Node negative
 Small cancer
 Low grade
 ER+

9. The new paradigm
 Size doesn’t matter
 Nodal status may or may not matter
 Phenotype (ER, PR, HER2) and biology
matter
 These apply not only to natural history but
to responsiveness to treatment

10. Prognostic/Predictive
variables
 Lower risk
 Older (menopausal)
 Small T
 NN
 Grade 1,2
 ER 2-3+
 Her2 negative
 Higher risk
 Younger
(premenopausal)
 Larger T
 Node positive
 Grade 3
 ER 1+ or ER negative
 Her2 positive
 LVI

11. Premenopausal ER+ breast
cancer
38y premenopausal woman post partial
mastectomy for 1.8cm, grade 3, ER 2+, PR-,
HER2-, node negative ductal cancer with
lymphatic invasion (LVI).
 Hormone therapy: if ER and/or PR positive
 Chemotherapy: determined by recurrence risk
 Clinical predictors for recurrence: grade, LVI, young
age
 Clinical predictors for benefit from treatment: ER
(hormone therapy); ?age, grade (chemo)

12. Menopausal case:
68y menopausal woman post mastectomy for 2.7cm,
grade 1, ER3+, PR 3+, HER2-, 1 node positive
ductal carcinoma.
Co-morbidities HTN, diabetes, high cholesterol,
overweight
Medications: ramipril; metformin; lipitor
 Grade, strong ER/PR, and node negative predict for low
recurrence
 Grade, strong ER/PR, age predict for low benefit from
chemo
 Age, comorbidities predict for lack of survival benefit from
chemo

13. Molecular subtypes
 Luminal A: ER+, low Ki67, her2-
 Luminal B: ER+, high Ki67, her2-
 Normal: ER+, Her2+
 Her2+: ER-, PgR-
 Basal: triple negative, EGFR+
Different gene exp’n, natural hx and response to
Rx. Basal are chemo sensitive but have worst OS.
Her2+ also have poor Px high prolif index
(influence of Herceptin)

14. Tools to help us
 PROGNOSTIC, (estimate risk): clinical
experience; adjuvant online; Oncotype
Dx Recurrence Score; intrinsic subtype
(luminal A vs B); Mammaprint; UPA,
PAI-1
 PREDICTIVE, (estimate benefit): clinical
experience; clinical trials; adjuvant
online; Oncotype Dx; PEPI score
(neoadjuvant hormone therapy)

15. Adjuvant online
Limitations:
• Her2 and LVI not adequately accounted for
• Less accurate for very small cancers, and very young pts

16. Microarray gene exp:
Oncotype DX
 21 gene expression panel (RNA expression
using RT-PCR: 16 cancer genes, 5 reference
genes NSABP B14: ER+, node
negative postmenopausal
women with TAM
NSABP B20: ER+ node
negative with TAM or CMF
and TAM
INT100: ER+
postmenopausal node
positive with TAM or TAM/
CAF
Other markers: MammaPrint; uPA, PAI-1

17. Oncotype Dx
Tissue based assay to assess risk in HR+ node
negative BC
Retrospective analyses suggest that for a
low and intermediate score, there is NO
additional benefit from chemotherapy

18. Oncotype Dx
 Recurrence score (RS) depends heavily
on ER and proliferation markers (grade
and degree of ER positivity are the poor
man’s Oncotype Dx)
 Generally weak ER+ cancers and higher
grade cancers will have a higher RS
 <5% of grade 1 cancers will have high RS
and 10% of grade 3 cancers will have a
low RS
 Not yet validated for NP premenopausal
BC

19. Hormone therapy

20. Hormone therapy options
Premenopausal
 Tamoxifen
 5 years
 10 years
 Switch to AI at 5y for
another 5y
(menopausal)
 Ovarian ablation + tam
 Ovarian ablation +
Aromatase Inhibitor
(AI)
Menopausal
 Early switch
 AI x 5 years
 Tam x 5 years
 Stop at 5 years
 Continue to 10 years
 Switch to AI at 5 years
for another 5 years
“Switch”: tamoxifen for 2-3 years followed by AI for balance of
5 years

21. Tamoxifen (T): mechanism of
action
, cells die
located in cell
nucleus
Effective in premenopausal and
postmenopausal women with ER+ BC
Role in primary prevention; adjuvant
therapy; metastatic disease
Partial agonist effects: bone;
endometrium; CVS
T
Estrogen can’t
bind

22. 5 years Tamoxifen
EBCTCG. Lancet 1998; Lancet 2005;365:1687; Reproduced with permission from Elsevier
NNT:
DFS: 8
OS: 11
• Magnitude
similar in all age
groups (<50,
50-69, 70+)
• Effect persists to
15 years
• Relapses
continue beyond
5 years follow up
RRR 28% RRR 28%

23. 10 years tamoxifen
Davies Lancet 2012

24. What about ovary
suppression
 EBCTCG:
 30% RRR death with oophorectomy vs not
 no benefit to oophorectomy if chemo given
 ZIPP study
 No added benefit to adding oophorectomy to TAM
 ABCSG 12
 Equivalent benefit from TAM and ANA with LHRHa
(no chemo)
 SOFT/TEXT
 EXE superior to TAM when combined with LHRHa
regardless of chemo use

25. Nuances…
 If TAMOXIFEN x5y is the standard:
 Are tam and OA the same?
 Are two hormone therapies better than one?
 What about when there are contraindications
or harm from tamoxifen
 VTE
 Endometrial cancer
 Depression
 Contribution of bisphosphonates to hormone
therapy?

26. Aromatase Inhibitors ( )
Androstenedione Testosterone
Aromatase Aromatase
Estrone Estradiol
Estrone sulphate
Postmenopausal women: Major source of total body estrogen
Premenopausal women: Minor source of total body estrogen
ANASTROZOLE (ARIMIDEX)
LETROZOLE (FEMARA)
EXEMESTANE (AROMASIN)
Reversible inhibitors
Irreversible inhibitor

27. Adjuvant AI meta-analysis
 Compared with 5 years of tamoxifen:
 3% improvement in DFS with AI x5y
1.1% NON-significant difference in BC-mortality
 3% improvement in DFS with switch
0.7% improvement in BC-mortality
 DFS = relapse, new CLBC, death from any
cause
NNT = 33 (SWITCH or AI 5y instead of 5y TAM)
NNT = 6 (SWITCH or AI 5y instead of No hormone therapy)
Dowset, JCO 2010

28. More than 5 years hormone
therapy
5 vs 10 years Tamoxifen
5 y of letrozole or
placebo after 5 y
tamoxifen
Atlas study, Lancet
2012
MA.17 study, JCO 2011
Overall survival benefit of 10 vs 5 years hormone therapy:
2-4%

29. Extended Adjuvant: MA17
RESULTS DFS HR 95% CI or p
value
OS HR
95% CI or p
value
ALL* 60m
30m
0.68
0.58
P<0.00005
P<0.0004
0.88
0.82
P0.37
P0.3
Node Neg 0.45 (0.27-0.75) NS _
Node Pos
0.61 (0.45-0.84) 0.61 (0.38-0.98)
*Absolute difference in DFS 6%

30. Chemotherapy

31. Premenopausal ER+ breast
cancer
38y premenopausal woman post partial
mastectomy for 1.8cm, grade 3, ER 2+, PR-,
her2-, LVI positive, NN ductal cancer
 Chemotherapy: determined by recurrence risk
 Hormone therapy: if ER and/or PR positive
 Clinical predictors for recurrence: grade, LVI, young
age
 Clinical predictors for benefit from treatment: ER
(hormone therapy); ?age, grade (chemo)

32. Menopausal case:
68y menopausal woman post mastectomy for 2.7cm,
grade 2, ER3+, PR 3+, her2-, NN ductal
carcinoma.
Co-morbidities HTN, NIDDM, high cholesterol,
overweight
Medications: ramipril; metformin; lipitor
 Grade, strong ER/PR, and node negative predict for low
recurrence
 Grade, strong ER/PR, age predict for low benefit from
chemo
 Age, comorbidities predict for lack of survival benefit from
chemo

33. Consider chemo
 ~Always
 Triple negative (ER,
PR, HER2 negative)
 HER2+
 Grade 3
 <45y and T2+
 >3 nodes positive
 ~Usually
 Weak ER positive
 Young and 1-3 node
pos
 Older, healthy, and 1-3
node pos and other
worry (high grade,
weak ER, LVI…)

34. Anti HER2 therapy
 HER2+ breast cancer: more aggressive, high
recurrence rates, very sensitive to chemo/
antiHER2 antibodies
 Normal cardiac function: small incidence of
cardiac injury, often reversible
 Chemotherapy planned: trivial benefit without
chemo
 Standard of care: 1 year of trastuzumab
 Future standard of care:
 Low risk: 3 months chemo, 1 year trastuzumab
 Intermediate risk: 6 months chemo, 1 year
trastuzumab
 High risk: 6 months chemo, 1 year trastuzumab,
pertuzumab

35. Chemotherapy timing
 Adjuvant = neoadjuvant
 Neoadjuvant advantages
 Local downstaging (locally advanced)
 Tests in vivo sensitivity

36. Chemotherapy primer
 Anthracycline based: AC, FEC, FAC
 BRAJAC; BRAJFEC; BRAJFAC
 Anthracycline free: DC, CMF, TCH
 BRAJDC; BRAJCMF; BRAJDCARBT
 Anthracycline + taxane: (AC-T), ddAC-T,
AC-D, AC-wT, FEC-D
 (BRAJACT); BRAJACTG; BRAJACTW;
BRLAACD; BRAJFECD

37. Node negative
 DC or AC or FEC
 ER+
 Older (>65)
 Her2 negative
 grade 3 but T1
 Cardiac risk (DC)
 LVI
 Anthracycline +
Taxane
 Triple negative
 Younger
 Her2 positive
 Grade 3 but T2+
 LVI

38. Node positive
 Anthracycline-taxane
 BRAJACT-G (needs GCSF) and BRAJACTW (no
GCSF) have the lowest toxicity coupled with best
efficacy
 BRAJACT (q3weeks) is antiquated (lower efficacy)
but often given in her2+ so trastuzumab can be
conveniently added to every 3 weeks
 BRAJFEC-D is an option, but D (docetaxel) has high
haem toxicity and needs G-CSF
 BRLAACD typically used for locally advanced (stage
III) due to higher heam toxicity with D.

39. Node positive
 Coverage for GCSF
 BRAJACT-G (q2w)
 BRAJFECD
 BRLAACD
 No coverage for
GCSF
 BRAJACTW (q1w T)
 BRAJACTT (if her2+)
 BRAJDCARBT (if
her2+ and cardiac
worry)

40. Anti-her2 therapy
 12 months trastuzumab standard of care
 Finher
 Phare
 Addition of pertuzumab or lapatinib
increases pCR in neoadjuvant therapy
 Pertuzumab/trastuzumab/chemo approved in
neoadjuvant therapy in US based on
neosphere and gepartquinto studies

41. Adj H trial designs: 1year
TRIAL N DESIGN
NCCTG N9831
3351
N=1616
AC → T q3w
AC → T q3w H qw
(AC → T → H )
NSABP B31
N=1736
AC → 12Tweekly
AC → TH
HERA 3388
(5090)
Chx → observation
Chx → 1y H q3w
Chx → 2y H
BCIRG 006* 3222 AC → D (q3w)
AC → DH
DCH
*D= docetaxel; T= paclitaxel

42. Meta-analysis of adj H trials
Viani G, BMC Cancer 2007
H No H Odds
ratio TR
vs no TR
CI Test for
hetero’y
P value
Mortality,n (%) 217/4555
(6)
392/4562
(8.5)
0.52 .44-.62 .28 <0.0001
Recurrence 400/4555
(8.2)
700/4562
(15.3)
0.53 .46-.6 .36
Cardiac grade
3,4
203/4555
(4.5)
86/4562
(1.8)
2.45 1.89-3.1
6
0.0001
Metastases 276/4555
(6)
497/4562
(10.8)
.34 0.00001
Brain mets 54/3365 30/3773 1.82 .5
Other cancer .33 .15-.74 .16

43. When to start chemo
 Wound healed, no ongoing infection
 3-10 weeks post surgery is ideal
 Reduced benefit if >12 weeks from
surgery
 Can defer re-excision of margins,
completion axillary dissection until post
chemo if high risk and result will not
influence chemo choice

44. Venous Access
 Typically we avoid the affected arm
 Practically, for those with Sentinel node
biopsy, lymphedema risk is only 1-2%, so can
use both arms
 Consider port for multiple iv start regimens
 Weekly chemo: 16 IV starts over 6 months
 HER2+: 21 IV starts over 15 months
 Anyone with needle phobia or poor venous access
 Epirubicin can sclerose veins; doxorubicin,
cyclophopshamide, and taxanes typically do
not

45. Chemotherapy Side Effects
 Educate pts
 What to expect
 When to expect onset, peak, resolution
 When and who to call

46. Hair Loss
 Alopecia: all adjuvant chemo regimens for BC
 Starts about 2 weeks after first dose
 Scalp: ~ 100%
 Eyelashes, eyebrows, body hair: Variable but frequent
 Most Extended Health Benefits will reimburse wig
 Pt needs a signed prescription “for chemo induced alopecia”
 Prevention: ice cap and tourniquet
 Used in Europe; impractical for infusions >1h (paclitaxel)
 Regrowth: 6-8 months to a short crop
 No regrowth: subtotal alopecia in 3% of docetaxel
treated pts

47. Nausea and Vomiting
 Anthracyclines, iv cyclophosphamide, carboplatin
 Acute phase peaks and recedes within 3 days
 Often worse in younger pts, pts who have had
morning sickness, are prone to motion sickness
 Ondansetron, dexamethasone pre and post dose
 Nausea, vomiting despite premeds:
 Ongoing: IV hydration and anti-emetics if needed
 Next cycle:
 add Aprepitant (EMEND) 125mg pre, 80mg day 2, day 3
 Ondansetron, dexamethasone IV, +/- ativan
 Late nausea: >3 days
 Is it heartburn, malaise, constipation, intercurrent illness?
 Breakthrough meds: metoclopramide, prochlorperazine
 Continue dexamethasone 1-2 days longer

48. Heamatologic effects
 Heamatologic
 WBC and neutrophils:
 Counts drop with all regimens
 Least impact with weekly dosing (paclitaxel)
 Highest impact with docetaxel
 Pt to be assessed for febrile neutropenia if T>38 Celcius
 Hemoglobin
 Modest drops with anthracyclines, taxanes
 Can contribute to fatigue
 Transfusion rarely needed
 Platelets
 Carboplatin
 Trastuzumab (rare)
 Concurrent G-CSF
G-CSF; dose reduction;
delay
Replace iron if needed,
monitor
Delay; dose reduce;
monitor

49. Peripheral Neuropathy
 Numbness, tingling (+/-painful):
 sensory (glove, stocking) and motor
 Cumulative dose related
 Taxanes, carboplatin
 Paclitaxel worse than docetaxel
 Weekly worse than q3w or q2w dosing
 Often worse for several months after chemo ends
 Small % permanent
 Monitor for function loss, or pain
 Dose reduce; stop; gabapentin

50. Cardiac
 Anthracyclines
 Cumulative dose related
 Dilated cardiomyopathy
 Older pt, cardiac co-morbidity
 Baseline LVEF if at risk
 Usually irreversible
 Myocyte damage by
oxygen radicals
 Not safe to rechallenge
 Standard CHF, low LVEF
management (ACE-I/ARB;
B-block; diuretics;
conditioning)
 Trastuzumab
 Dose independent, often
early
 Dilated cardiomyopathy
 Older pt, borderline
function
 Baseline LVEF in all
 Usually reversible/partly
rev
 Idiosyncratic, mechanism
unknown
 Algorhythm in protocols to
continue, stop, rechallenge
based on evolving LVEF,
symptoms
 Standard CHF, low LVEF
management

51. Mucositis (mouth sores)
 All drugs, worst with anthracyclines,
cyclophosphamide
 Any pt can get mouth sores
 Generally confined to mouth, but can get sore
throat
 Prophylactic baking soda mouth rinse bid
 Magic mouthwash
 Thrush overgrowth uncommon
 Lower incidence in pts on G-CSF

52. Infusion reactions
 Usually during infusion
 Many culprit drugs
 Taxanes:
 Paclitaxel > Docetaxel >>> Abraxane
 Anaphylactic, mild-severe spectrum
 Stop infusion, steroids, benadryl, ventolin, oxygen, monitor
(epinephrine)
 Can often resume at lower infusion rate and complete
 Recurrent with future infusions
 Pre-medicate future doses with hydrocortisone 100mg iv
 Trastuzumab:
 first infusion only
 Anaphylactoid, generally mild
 Can occur during immediate post infusion period
 No need to pre-medicate future doses
 (ARDS-type rxn in metastatic disease with high lung burden – rare)

53. Menopause, Amenorrhea
 Anthracycline, cyclophosphamide total dose and
patient age
 AC-T in a 38 yo: 30% menopause 47 yo: 80% menopause
 FEC in a 38 yo: 50% menopause 47 yo: 95%
menopause
 Affects fertility even without permanent amenorrhea
 Embryo banking for young women who want kids
 LNMP often in cycle 1, 2
 Resumption of menses can take up to 2-3 years
 Post treatment Estradiol, LH, FSH levels do not
predict future recovery
 For hormone therapy, if premenopausal at Dx, give
tamoxifen, not AI even if amenorrhea from chemo
 Better DFS if permanent menopause in ER+ BC

54. Chemo Brain
 Mechanism not well understood
 Not predictable by patient or regimen
 Multifactorial:
 Menopause
 Fatigue
 Depression, worry, anxiety, pre-occupation
 Poor sleep
 Chemo
 multi-tasking, short-term memory,
concentration fatigue, processing speed
 Variable resolution, frequently persistent

55. Nail Changes
 Fingers/toes
 All drugs but worst with docetaxel, paclitaxel.
 Dark lines, splitting, lifting, oozing, loosing,
ridges
 Frozen gloves with docetaxel very effective
 Soak in warm salt water if oozing
 Changes resolve slowly (months)

56. Myalgias, Arthralgias
 During chemo:
 Taxanes: paclitaxel q3w > weekly > docetaxel
 Days 3-7
 Gapabentin; tylenol; opioids
 recurrent
 G-CSF: usually lessens with subsequent dosing
 After chemo:
 Aromatase inhibitor
 Rule out unmasked arthritis
 Autoimmune / rheumatoid type multi-joint pain
 Infrequent ?3%
 Occasionally severe enough to need steroids
 Usually resolves gradually with no permanent changes to
joints

57. Taste and Weight
 Weight gain common:
 Steroids
 Menopausal changes
 Change in routine (not working, less exercise, comfort
eating)
 Depression, anxiety alter metabolism
 Hormone therapy may alter metabolism
 Taste: temporary
 “food tastes metallic” “everything is sweet”
 “things taste like wood”
 “my mouth is so dry I can’t swallow”

58. Work and Chemo
 Is it safe to work?
 No significant risk to self, co-workers, family
 Is it sensible to work?
 Multiple appointments
 Transient side effects at different times, cumulative
 Emotional roller coaster
 Decreased physical and mental stamina
 When is return to work reasonable?
 3-6 months post chemo or radiation (whichever is last)
 When hormone therapy side effects adjusted to
 Graduated hours return is optimal
 Some have lasting fatigue and cannot return to former work level

59. Summary
 Majority of women in BC have early stage
and highly curable breast cancer
 Treatment is multi-disciplinary (surgery,
radiation, hormone, chemo, antiHER2)
 A few side effects are permanent or long
lasting, most are temporary
 Women need support through treatment
(anxiety, menopausal symptoms, body
image, depression, loss of control)

60. Questions?