This document provides an overview of breast cancer therapy. It discusses trends in breast cancer incidence in the United States, declining mortality rates, and treatment approaches for early stage disease including local and systemic therapies guided by risk assessment. Key aspects of risk assessment using tools like Oncotype DX are outlined. The roles of endocrine therapy and chemotherapy in adjuvant treatment are summarized, including evolving regimens and trial results demonstrating improved outcomes. Potential toxicities of different systemic therapies are also highlighted.

1. Breast Cancer 101:
an overview of therapy
Tiffany A. Traina, MD
Breast Cancer Medicine Service
April 2011
The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The
slides are courtesy of Dr. Tiffany Traina and were updated for the LibGuide in 2011-2012 .

2. New Invasive Breast Cancer Cases
United States 2010 Estimates
207,090 invasive ca
54,010 in situ ca

3. Breast cancer mortality is declining

4. Treatment of Early Stage Disease
Curative intent!
Local therapy
Risk assessment
Systemic therapies

5. What do we need to know from
pathology to estimate risk?
• T • Don’t sweat the
• N staging!
• ER/PR – LN-
– LN+
• HER2
– MBC
– IHC
– FISH
• Margins
• LVI, Grade

6. History of Risk Assessment
• Traditional prognostic factors
– Limited predictive power (T 10% N 5% rule)
– Poor reproducibility
– Lack standardization, validation
– Limited insight into relative benefits of
chemotherapy for different individuals
Bundred. Cancer Treat Rev. 2001;27:137-142.

7. Risk Assessment
www.adjuvantonline.com
60yo healthy woman with:
T1 (0.1-1cm), N0
Grade 2 IDC
ER(+)

8. Risk Assessment
www.adjuvantonline.com
40yo healthy woman with:
T2 (2.1-3cm), N1,
Grade 3 IDC
ER(-)

9. Why we need better
risk assessment tools?
• Only 15% of LN(-) patients recur BUT
– 50% of these patients receive chemotherapy!
• Rationale for predictive/prognostic
technologies:
– Avoid Over-treatment
– Avoid Under-treatment
• Potential economic benefits

10. Oncotype DX™
• 21 gene RT-PCR assay on FFPE tumor
• Prognostic:
– Estimates risk of breast cancer recurrence
• Predictive:
– What added benefit from chemotherapy
• ER(+), Lymph node (-) cancers
• “Recurrence score”= risk of recurrence in 10yrs
• Some data for its use in LN(+), but too early to
change practice (Albain SABCS 2007)
Paik et al, NEJM 2004 Dec 30;351(27):2817-26.

11. What is this patient’s risk of recurrence?

12. Low Recurrence Score: 4
Rate of Distant Recurrence at 10 Yrs: 5%

13. TAILORx closed to accrual
N=11,000+ patients

14. Early Stage Breast Cancer
Systemic Therapy
• Endocrine therapy
– Tamoxifen
– Aromatase Inhibitors
• Chemotherapy
– Anthracycline-based
– Anthracycline- & Taxane-based
• Biologic therapy
– Trastuzumab

15. Endocrine Therapy:
The oldest targeted therapy
SERMs E
Aromatase
(ie, tamoxifen) Steroid
inhibitors
precursors
(ie, letrozole,
anastrozole)
ER ER
ER antagonist
(ie, fulvestrant)

16. Tamoxifen Improves DFS & OS
Recurrence Breast Cancer
Mortality
EBCTCG, Lancet 365:1665, 2005

17. Aromatase Inhibitors
↓ Estrogen Synthesis
Cholesterol
Cortisol
Pregnenolone
Progesterone Androstenedione Testosterone
Aromatase
Aldosterone Enzyme
Complex
Estrone Estradiol

18. AI Trial Designs
DIRECT COMPARISON SUPPORTING TRIALS
• ATAC
• BIG FEMTA
SWITCHING SUPPORTING TRIALS
• IES
• ITA
* • ARNO/ABCSG
EXTENDED ADJUVANT
SUPPORTING TRIALS
• MA-17
• ABCSG-6A
* • NSABP B33
SEQUENCING SUPPORTING TRIALS
• No reported trials
• BIG FEMTA
• TEAM

19. AIs improve DFS over Tam
Med. f/u
N (mo) DFS (HR, p) OS (HR, p)
ATAC 6241 SABCS 2007 100 0.85 (0.003) 0.97 (0.7)
Up-Front
BIG-1-98 4922 JCO 2007 51 0.82 (0.007) 0.91 (>0.05)
ITA-1 380 JCO 2001 61 NR NR
Ann Oncol
ITA-2 448 64 0.57 (0.005) 0.56 (0.1)
2006
“Early”
Switch IES 4742 Lancet 2007 56 0.76 (0.0001) 0.85 (0.08)
ABCSG8/ARNO 3224 Lancet 2005 28 0.60 (0.0009) NR
MA.17 5157 JNCI 2005 30 0.58 (0.001) 0.82 (0.3)
“Extended”
ABCSG 6a 856 ASCO 2005 60 0.64 (0.047) NR
Switch
NSABP B-33 1598 SABCS 2006 30 0.68 (0.07) 1.20 (0.64)

20. Safety of Anastrozole vs. Tamoxifen
On Treatment Off Treatment
Serious Adverse Anastrozole Tamoxifen Anastrozole Tamoxifen
Events
Treatment Related 153 284 49 57
Endometrial 4 12 1 12
Cancer
Myocardial 34 33 26 28
Infarction
Cerebrovascular 20 34 22 20
Accident
Fracture Episode 375 234 146 143
• Relative risk of fracture episode at 5 years = 1.55; P < .0001
• Relative risk of fracture episode at 9 years = 1.03; P = 0.79
• No excess fracture episodes or new morbidities after completion
of anastrozole
Forbes et al. Breast Cancer Res Treat 2007; 106 (suppl 1): S12 (abstract 41)
Howell et al. Lancet Oncol. 9: 45-53, 2008

21. Adjuvant AI Trials: Toxicity
Tamoxifen AI
– Genitourinary bleeding – Bone loss/Osteoporosis
– Endometrial cancer – Bone fracture
– DVT/CVA etc – Arthralgia/myalgia
• More or less similar
– Hot flashes / night sweats
– Headache / dizziness
– GI side effects
– Compliance

22. Chemotherapy

23. Adjuvant Chemotherapy:
What We Know
• Chemotherapy improves DFS and OS
• Polychemotherapy x3-6 months
• Anthracycline-containing regimens > CMF
• Anthracycline and Taxane-containing regimens >
anthracycline-containing regimens
• Chemotherapy and hormonal therapy benefits are
independent

24. History of Adjuvant Chemotherapy
1970’s • Improvement in disease free survival for LN+ BC
• Single agent vs. various drug combinations
• Sequencing of single agents & drug combinations
• Evaluation of dose intensity
• Improvement in DFS for LN- BC
1980’s • Greater use of anthracyclines
• Introduction of taxanes
1990’s • Dose intensive regimens +/- stem cell support
• “dose-dense” plus colony stimulating factors
• Role of prognostic factors in choosing therapy
2000’s • Biologic therapies – trastuzumab
• Oncotype/Mammaprint

25. Improved Survival with Polychemotherapy
15 Years of Follow-Up
10% gain
12% gain
EBCTCG Lancet „05

26. Evolution of Adjuvant Chemotherapy
CMF = AC = FEC 50
(Milan) (B-15) (ICCG)
CEF FAC TC AC-P FEC 100
(MA-5) (GEICAM) (US 9735) (C 9344;B-28) (FASG 05)
AC-T AC2w- FEC-T
TAC (E 1199 AC-Pw P2w (PACS 01 FEC-Pw
(BCIRG 001, 005) BCIRG 005 (E 1199) (C 9741) EC-T (G 9906)
B-30) WSG)
Walshe et al, 2006; Ellis, 2006; Fumoleau et al, 2003; Roche et al, 2006; Eiermann et al, 2008; Mamounas, 2005; Joensuu et al, 2009.

27. Acute Toxicities of Chemotherapy
• Myelosuppression
• Gastrointestinal (mucositis, nausea, vomiting, diarrhea)
• Alopecia
• Fatigue
• Infections (febrile neutropenia)
• Cystitis
• Sterility/Chemical Menopause
• Cardiomyopathy (with anthracyclines)
• Neuropathy

28. Long-term complications of chemo
CHF
TAC
AC
Wouters et al, 2005.

29. Long-term complications of chemo
Hematologic malignancy
Anthracyclines:
2-4 years
Alkylators:
5-10 years

30. CMF

31. What is CMF?
• Cyclophosphamide, Methotrexate, 5FU
• 1st regimen to show improved DFS and OS
in adjuvant treatment of breast cancer
• Well-tolerated:
– fatigue, mild nausea or diarrhea
• Use has diminished with data showing
benefit of anthracycline-based therapy
EBCTCG. Lancet 352:930-942, 1998
EBCTCG Lancet 2005

32. When we consider CMF?
• Low-risk breast cancer
– Lymph node (-)
– ER/PR (+)
– HER2/neu “normal”
• Elderly patients
• Cardiac dysfunction
• Prior anthracycline

33. Anthracyclines

34. Anthracyclines Add Benefit in
Unselected, Node-Positive Disease
4.6%
3.7%
EBCTCG, Lancet 2005

35. Anthracycline-Based Regimens ↑DFS and OS
• Doxorubicin-based regimens:
– AC x 4
– CAF/FAC
– A CMF
• Epirubicin-based regimens:
– CEF/FEC
– E  CMF

36. What is Role of Taxanes in the
Adjuvant Setting?

37. Taxane Benefit in Unselected
Patients
• Taxane vs. no taxane:
Breast cancer death
– 5.1% ↓ over no taxane
• Built upon anthracycline
backbone
Peto et al, 2007.

38. CALGB 9344
5-yr DFS
N >3,000 pts 65% vs 70%
P=0.0023
A: 60 = 75 = 90 mg/m2
P 175 mg/m2 (3 h)
C: 600 mg/m2 5-yr OS
77% vs 80%
P=0.0064
Henderson et al. JCO 2003

39. Dose-Dense Chemotherapy

40. The Norton-Simon Hypothesis
Standard Regimen Dose-Dense Regimen
1012 1012
Cell Number
108 108
Cell Number
104 104
100 100
0 20 40 60 0 20 40 60
Weeks Weeks

41. CALGB 9741 - INT C9741
2X2 Factorial Design q 2 wk +Filgrastim q 3 wk
SEQUENTIAL
24 weeks 36 weeks
SEQ Q2 SEQ Q3
CONCURRENT
16 weeks 24 weeks
CON Q2 CON Q3
doxorubicin 60 mg/m2
cyclophosphamide 600 mg/m2
paclitaxel 175 mg/m2 over 3 hours Citron JCO 2003

42. Overall Survival by Density
Overall Survival
By Density
1.0
q2
0.8
q3
Proportion Surviving
0.6
31% reduction in mortality
0.4
P=0.013
0.2
0.0
0 1 2 3 4
Years From Study Entry
q 2 wks N= 988 Events= 75
q 3 wks N= 985 Events= 107

43. E1199: Paclitaxel vs Docetaxel
Weekly vs Q 3 Week
dose/cycle total dose
(mg/m2) (mg/m2)
Paclitaxel (q3w vs. q1w)
175 700
80 960
100 400
35 420
Docetaxel (q3w vs. q1w)
N=4950
Primary Endpt=DFS
Sparano, NEJM 358:1663-1671. April 17, 2008

44. ECOG 1199: DFS
Comparison HR 95% CI p Value
Paclitaxel vs. docetaxel 1.032 0.91, 1.17 .61
q 3 wks vs. wkly 1.062 0.94, 1.20 .33
1.0
 No significant
0.9
difference by
taxane or schedule
0.8
DFS (%)
0.7
5-year DFS rates (No. Events)  Hint that best
------------------------------------------------------------ outcome in wkly
0.6
P3: 76.9% P1: 81.5% D3: 81.2% D1: 77.6% paclitaxel or q 3
wks docetaxel
0.5
0m 20 m 40 m 60 m 80 m
Sparano et al, 2008.

45. Making the Decision Based on Toxicity:
ECOG 1199 (Grade 3–4)
P3 (%) P1 (%) D3 (%) D1 (%)
Neutrophils 4 2 47 3
Febrile neutropenia < 0.5 1 16 1
Infection 3 3 13 4
Stomatitis < 0.5 0 5 2
Fatigue 2 3 9 11
Myalgia 7 2 6 1
Arthralgia 6 2 6 1
Tearing < 0.5 0 < 0.5 5
Grade 3–4 neuropathy 5 8 4 6
Grade 2–4 neuropathy 20 27 16 16
Sparano et al, 2008.

46. Do we need anthracyclines?

47. USO 9735: AC vs. TC
Doxorubicin 60 mg/m2 +
Stage I–III operable R cyclophosphamide 600 mg/m2
breast cancer AC q 3 wks
A
N = 1,016 N n = 510
20% stage I, 70% stage II D
70% HR+ O
50% N+ (40% 1–3, 10% 4+) M
I Docetaxel 75 mg/m2 +
Z TC cyclophosphamide 600 mg/m2
E n = 506
Primary objectives: DFS and OS at 7-year F/U
Jones et al, 2006, 2009.

48. TC > AC
26% improvement
in DFS
TC > AC
31% improvement
in OS
Jones et al, 2009.

49. Do We Need Polychemotherapy in
Older Patients?
CALGB 49907
Age > 65
(~ 60% > 70)
Randomize
Oral CMF x 6 Capecitabine (X) x 6
AC x 4 cycles
 Both arms tolerated but more toxicity in AC/CMF arm than X arm
SOG, 2010.

50. CALGB 49907: RFS
 Polychemotherapy still relevant even in older populations!
 Difference particularly marked in ER-
 Median F/u: 2-4 years
Muss et al, 2009.

51. Trastuzumab in the Treatment
of Her2(+) Breast Cancer

52. Trastuzumab:
humanized monoclonal Ab to HER2
Hudis CA. NEJM
2007;357:39-51

53. Pivotal Combination Trial of First-Line
Chemotherapy Trastuzumab
in MBC: Overall Survival
1.0
Trastuzumab + CT (n=235)
CT (n=234)
0.8
Proportion alive
0.6 25.1 mo
(median)
0.4 20.3 mo
(median)
0.2 RR=0.80
P=0.046
0
5 15 25 35 45
Months
Slamon et al. N Engl J Med. 2001;344:783.

54. Adjuvant Trastuzumab Trials
Anthracyclines and Adjuvant Trastuzumab
NSABP B-31 BCIRG 006
Doxorubicin
Cyclophosphamide
Paclitaxel
H…x 52 Docetaxel
H…x 52
Carboplatin
H…x 52 Epirubicin
NCCTG 9831 HERA Vinorelbine
No therapy Fluorouracil
H…x 52 Standard H Trastuzumab
ChemoRx H… x 1 year
H… x 2 years
H…x 52
FinHer PACS 04
H…x 52
H…x9
No therapy
H…x9
Romond et al, 2005; Slamon et al, 2006; Joensuu et al, 2009; Smith et al, 2007; Spielmann et al, 2007.
Courtesy of Clifford Hudis

55. 4-Year DFS Adjuvant
Trastuzumab Trials
DFS
Duration of Median
Study HR p Value
therapy F/U
T + CT CT alone
NSABP B-31/
1 year 4 years 86% 73% 0.49 < .0001
NCCTG N9831
84%: AC-TH 0.64 < .0001
BCIRG 006 1 year 65 mos 75%
81%: TCarboH 0.75 .004
HERA 1 year 4 years 79% 73% 0.76 < .0001
Perez et al, 2007; Slamon et al, 2009.

56. Adjuvant Trastuzumab Regimens:
Cardiotoxicity
% NYHA Class III-IV CHF
Study
Control arm Trastuzumab arm
NSABP B-31 0.8 4.1
N9831 0 2.9
HERA 0 0.6*
BCIRG 006** .95† 1.33‡ / 2.34§
FinHer¶ 0 0
*1-yr trastuzumab arm; **Includes: Grade 3 or 4 arrythmias, Grade 3 or 4 cardiac
ischemia / infarction; †AC T; ‡TCH; §AC TH; ¶Small sample size.

57. Adjuvant Trastuzumab: Cardiac Toxicity
and DFS Improvement
Nonanthracycline
Bird et al, 2008.

58. Risk Factors for Trastuzumab-
related Cardiotoxicity
•Prior use of anthracycline
• Age
• Baseline LVEF
• Hypertension medication use

59. Metastatic Breast Cancer
Lots of drugs work,
but we haven’t cured breast cancer yet

60. Chemo that “works” in breast cancer
• Taxanes • Irinotecan
– paclitaxel, docetaxel, nab- • Etoposide
paclitaxel
• Continuous infusion 5FU
• Anthracyclines
• Cis- or Carboplatin
–
doxorubicin, epirubicin, lip
osomal dox Biologics plus Chemo:
• Capecitabine – HER2+
• Ixabepilone • Trastuzumab
• Lapatinib
• Vinorelbine
– AntiVEGF
• Gemcitabine • Bevacizumab
• Eribulin

61. Basic concepts for MBC
• Goals are palliative so minimize toxicity while
improving response & survival
• For ER/PR+ MBC  start with and use hormones
as long as possible
– Tam, letrozole, anastrozole, exemestane, fulvestrant…
– Exception is rapidly progressing visceral mets
• Single, sequential agent therapy over
combinations
– Combinations = better response, more toxicity, not
necessarily longer survival than using same drugs in
sequence

62. Triple Negative and Basal-like
Breast Cancer

63. Triple-Negative Breast Cancer
 Defined as negative on
clinical assays for
– ER
– PR
– HER2 (c-erbB2, neu)
Approximately 25,000–30,000 cases per year in U.S.
but responsible for a disproportionate number of
deaths
Cleatore et al, 2007; ACS, 2009.

64. Intrinsic Breast Cancer Subtypes
 “Unsupervised” gene expression array analysis of unselected breast
cancers = intrinsic subtypes
 Intrinsic gene clusters identify
distinct subtypes
– Hormone receptor (luminal) cluster Subtypes
– HER2 “enriched” cluster with low
– Basal cluster expression
– Proliferative cluster of luminal ER-negative
and HER2 subtypes
clusters =
 When luminal and HER2
mostly
clusters low = usually ER-
basal-like
, PR-, and HER2- on clinical
assays  “triple-negative”
Image coutesy of Chuck Perou, MD.
Seal et al, 2010.

65. Basal-Like Breast Cancer and BRCA1
Basal-like
BRCA2
BRCA1 = BRCA1+T et = BRCA2+
Sorlie al. PNAS 03
• Most BRCA1 carriers get basal-like breast cancer
but
• Most basal-like breast cancers are not in BRCA1 carriers
Is BRCA1 pathway abnormal in sporadic
(noninherited) basal-like breast cancers?
Sorlie et al, 2003. Courtesy Lisa Carey

66. Jury is still out on platinums…
Byrski et al, 2010 Silver et al, 2010
• Neoadjuvant cisplatin pCR • Prospective trial of cisplatin
83% in BRCA1+ patients in 28 pts with
(n=12) BRCA1+/TNBC
• Retrospectively compared to • pCR 22%
historic standard • pCR 14% if non-BRCA1
neoadjuvant regimens (pCR • Unclear if this is platinum
7-22%) sensitivity or just
• Cisplatin arm has smaller chemotherapy sensitivity
tumors, more LN-negative

67. Targets for Triple-Negative Breast Cancer
Target Rationale Treatment
DNA DNA aberrations suggestive Chemotherapy-double
of defective DNA repair; strand DNA breaks,
selective chemosensitivity such as platinums
PARP1 DNA aberrations suggestive PARP inhibitors
of defective DNA repair
EGFR Overexpression of EGFR Cetuximab, erlotinib
Src Sensitivity to dasatinib Dasatinib
Androgen Expression in 15% of triple- Bicalutamide
receptor negative tumors
Adapted from Cleator S et al. Lancet Oncology 8:235-244, 2007

68. Poly(ADP-Ribose) Polymerase (PARP)
• A key role in the repair of DNA single-strand breaks
• Through the base excision repair pathway (BER)
• Binds directly to sites of DNA damage
• Once activated, it uses NAD as a substrate, and generates large, branched
chains of poly (ADP-ribose) polymers on multiple target proteins
• Recruits other DNA repair enzymes
• PARP-inhibition prevents recruitment of DNA repair enzymes  failure of
single strand break repair  accumulation of ssDNA breaks
• During S-phase, this leads to arrest of the replication fork at site of ssDNA
break and degeneration to dsDNA breaks. Normal cells can then repair
dsDNA break using homologous recombination
Helleday T et al. Cell Cycle 2005; 4: 1176-1178.

69. Randomized Phase II Trial of
Gemcitabine and Carboplatin BSI-201 in TNBC
Gemcitabine (1000 mg/m2 IV d1, 8)
Eligibility Carboplatin (AUC 2 IV d 1, 8)
q21 days
• Metastatic TNBC with
measurable disease
• 0-2 prior chemotherapy R BSI-201 (5.6 mg/kg IV D1, 4, 8, 11)
regimens for metastatic
disease Gemcitabine (1000 mg/m2 IV d1, 8)
N = 123
Carboplatin (AUC 2 IV d 1, 8)
q21 days
Primary Endpoint: Clinical benefit rate (CR + PR + SD 6 mo)
O’Shaughnessy J et al. J Clin Oncol 2009;27(18S):793s (abstr 3)

70. 2009 SABCS Update:
Overall Survival
O’Shaughnessy J et al. SABCS 2009;(abstr 3122)

71. TNBC Treatment
• No defined standard of care for metastatic
or adjuvant treatment of TNBC
• Subset analyses suggest TNBC benefits
from antiangiogenic therapy
• Current trials determining the role of PARP
inhibition and platinum agents in this
subtype of breast cancer