Adjuvant systemic therapy Breast cancer

Survival after early breast cancer

Survival in BC: Best in Canada and similar to Australia, Sweden

Improvements over time:

adjuvant taxanes, AIs (2000+)

Adjuvant trastuzumab (2005+)

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

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

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

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

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

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+

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

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

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)

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

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)

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)

Adjuvant online

Limitations:

• Her2 and LVI not adequately accounted for

• Less accurate for very small cancers, and for

very young pts

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

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

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

  Useful for clinically intermediate risk ER+, NN cancers as decision aid for chemo vs not

Hormone therapy

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

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

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%

10 years tamoxifen

Davies Lancet 2012

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

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?

Aromatase Inhibitors ( )

Androstenedione Testosterone

Estrone Estradiol

Aromatase Aromatase

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

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

Dowset, JCO 2010

  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)

More than 5 years hormone therapy

5 vs 10 years Tamoxifen 5 y of letrozole or placebo after 5 y tamoxifen

Overall survival benefit of 10 vs 5 years hormone therapy: 2-4%

Atlas study, Lancet 2012

MA.17 study, JCO 2011

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%

Chemotherapy

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)

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

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…)

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

Chemotherapy timing

  Adjuvant = neoadjuvant   Neoadjuvant advantages

  Local downstaging (locally advanced)   Tests in vivo sensitivity

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

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

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.

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)

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

Adj H trial designs: 1year

TRIAL N DESIGN

NCCTG N9831 N=1616

3351

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

Meta-analysis of adj H trials 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 1.89-3.16

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

Viani G, BMC Cancer 2007

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

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

Chemotherapy Side Effects

  Educate pts   What to expect   When to expect onset, peak, resolution   When and who to call

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

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

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

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

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

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

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)

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

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

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)

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

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”

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

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)

Questions?