This document discusses adjuvant systemic therapies for breast cancer, focusing on the evolution of treatments and survival rates. It emphasizes the importance of personalized treatment plans based on tumor biology, patient demographics, and risk factors, integrating traditional and modern prognostic evaluation tools. The document also outlines various treatment regimens, surgical options, and the implications of hormone therapy and chemotherapy in different patient scenarios.

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?